US11759481B2 - Methods and compositions relating to exosomes - Google Patents
Methods and compositions relating to exosomes Download PDFInfo
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- US11759481B2 US11759481B2 US16/814,044 US202016814044A US11759481B2 US 11759481 B2 US11759481 B2 US 11759481B2 US 202016814044 A US202016814044 A US 202016814044A US 11759481 B2 US11759481 B2 US 11759481B2
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Definitions
- Exosomes are cell-derived vesicles that are present in many and perhaps all biological fluids, including blood, urine, and conditioned media from cell cultures.
- the reported diameter of exosomes is typically between 30 and 100 nm, which, for comparison, is larger than LDL but significantly smaller than red blood cells.
- Exosomes are known to be released from cells when multivesicular bodies fuse with the plasma membrane or when they are released directly from the plasma membrane. It is becoming increasingly clear that exosomes have specialized functions and play a key role in, for example, coagulation, intercellular signaling, and waste management. Consequently, there is a growing interest in the clinical applications of exosomes, including synthetic exosomes which recapitulate aspects of cell-derived exosomes. Exosomes can potentially be used for prognosis, therapy, and biomarkers for health and disease.
- compositions comprising exosomes and methods of use thereof in the treatment and/or prevention of various diseases or disorders.
- the isolated exosome comprises one or more markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105, and/or the isolated exosome does not comprise one or more markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome comprises 2, 3, 4, 5, 6, 7 or 8 markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105.
- the isolated exosome comprises the markers ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, the isolated exosome does not comprise 2, 3, 4, 5, 6 or 7 markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2. In some embodiments, the isolated exosome does not comprise the markers FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome has spherical morphology and appears radiolucent upon negative staining in transmission electron microscopy, and/or the isolated exosome does not have a cup shape morphology in negative staining transmission electron microscopy.
- the isolated exosome may have a diameter of about 10-150 nm. In some embodiments, the isolated exosome has a diameter of about 30-100 nm.
- the isolated exosome is isolated from a mesenchymal stem cell (MSC), fibroblast, or macrophage. In some embodiments, the MSC, fibroblast, or macrophage is a human MSC, human fibroblast, or human macrophage.
- the MSC is isolated from Wharton's jelly, umbilical cord blood, placenta, peripheral blood, bone marrow, or adipose tissue.
- the isolated exosome is comprised in a composition.
- the composition is a pharmaceutical composition.
- an isolated exosome comprises one or more markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2, and/or the isolated exosome does not comprise one or markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105.
- the isolated exosome comprises 2, 3, 4, 5, 6 or 7 markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome comprises the markers FLOT1, CD9, CD81, CAV1, EGFR, and AKT1 and AKT2. In some embodiments, the isolated exosome does not comprise 2, 3, 4, 5, 6, 7 or 8 markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, the isolated exosome does not comprise the markers ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5, and CD105.
- the isolated exosome has cup shaped morphology in negative staining transmission electron microscopy and/or does not have a spherical morphology in negative staining transmission electron microscopy. In some embodiments, the isolated exosome has a diameter of about 10-250 nm. In some embodiments, the isolated exosome has a diameter of about 30-200 nm.
- a method for treating a lung disorder, a cardiovascular disorder, a renal disorder, or an ischemic neural disorder comprises administering to a subject having or at risk of having a lung disorder, a cardiovascular disorder, a renal disorder, or an ischemic neural disorder a therapeutically effective amount of an isolated exosome.
- the isolated exosome comprises one or more markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105, and/or the isolated exosome does not comprise one or more markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome comprises 2, 3, 4, 5, 6, 7 or 8 markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, the isolated exosome comprises the markers ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, the isolated exosome does not comprise 2, 3, 4, 5, 6 or 7 markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome does not comprise the markers FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome has spherical morphology and appears radiolucent upon negative staining in transmission electron microscopy and/or the isolated exosome does not have a cup shape morphology in negative staining transmission electron microscopy.
- the isolated exosome has a diameter of about 10-150 nm. In some embodiments, the isolated exosome has a diameter of about 30-100 nm. In some embodiments, the isolated exosome is isolated from a mesenchymal stem cell (MSC), fibroblast, or macrophage.
- MSC mesenchymal stem cell
- the MSC, fibroblast, or macrophage is a human MSC, human fibroblast, or human macrophage.
- the MSC is isolated from Wharton's jelly, umbilical cord blood, placenta, peripheral blood, bone marrow, or adipose tissue.
- the lung disorder being treated is inflammatory lung disease, lung vascular disease, or acute lung injury.
- the inflammatory lung disease is hypoxia-induced lung inflammation, pulmonary hypertension, asthma, bronchopulmonary dysplasia (BPD), allergy, or idiopathic pulmonary fibrosis.
- the acute lung injury is associated with sepsis or is ventilator-induced acute respiratory distress syndrome (ARDS).
- ARDS ventilator-induced acute respiratory distress syndrome
- a cardiovascular disorder being treated according to the method is myocardial infarction, cardiovascular disease, hypertension, atherosclerosis, or heart failure.
- the renal disorder is ischemic renal injury, acute renal failure, or renal fibrosis.
- the disorder is hypoxic ischemic encephalopathy or ischemic stroke.
- an isolated exosome for treating a lung disorder, a cardiovascular disorder, a renal disorder, or an ischemic neural disorder.
- the isolated exosome comprises one or more markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105, and/or the isolated exosome does not comprise one or more markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome comprises 2, 3, 4, 5, 6, 7 or 8 markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, the isolated exosome the markers ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, the isolated exosome does not comprise 2, 3, 4, 5, 6 or 7 markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2. In some embodiments, the isolated exosome does not comprise the markers FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome has spherical morphology and appears radiolucent upon negative staining in transmission electron microscopy and/or the isolated exosome does not have a cup shape morphology in negative staining transmission electron microscopy.
- the isolated exosome has a diameter of about 10-150 nm. In some embodiments, the isolated exosome has a diameter of about 30-100 nm.
- the isolated exosome is isolated from a mesenchymal stem cell (MSC), fibroblast, or macrophage.
- the MSC, fibroblast, or macrophage is a human MSC, human fibroblast, or human macrophage.
- the MSC is isolated from Wharton's jelly, umbilical cord blood, placenta, peripheral blood, bone marrow, or adipose tissue.
- the lung disorder is inflammatory lung disease, lung vascular disease, or acute lung injury.
- the inflammatory lung disease is hypoxia-induced lung inflammation, pulmonary hypertension, asthma, bronchopulmonary dysplasia (BPD), allergy, or idiopathic pulmonary fibrosis.
- the acute lung injury is associated with sepsis or is ventilator-induced acute respiratory distress syndrome (ARDS).
- the cardiovascular disorder is myocardial infarction, cardiovascular disease, hypertension, atherosclerosis, or heart failure.
- the renal disorder is ischemic renal injury, acute renal failure, or renal fibrosis.
- the ischemic neural disorder is hypoxic ischemic encephalopathy or ischemic stroke.
- an isolated exosome in the manufacture of a medicament for treating a lung disorder, a cardiovascular disorder, a renal disorder, or an ischemic neural disorder.
- the isolated exosome comprises one or more markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105, and/or the isolated exosome does not comprise one or more markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome comprises 2, 3, 4, 5, 6, 7 or 8 markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, the isolated exosome comprises the markers ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, the isolated exosome does not comprise 2, 3, 4, 5, 6 or 7 markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome does not comprise the markers FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome has spherical morphology and appears radiolucent upon negative staining in transmission electron microscopy; and/or the isolated exosome does not have a cup shape morphology in negative staining transmission electron microscopy.
- the isolated exosome has a diameter of about 10-150 nm. In some embodiments, the isolated exosome has a diameter of about 30-100 nm. In some embodiments, the isolated exosome is isolated from a mesenchymal stem cell (MSC), fibroblast, or macrophage.
- MSC mesenchymal stem cell
- the MSC, fibroblast, or macrophage is a human MSC, human fibroblast, or human macrophage.
- the MSC is isolated from Wharton's jelly, umbilical cord blood, placenta, peripheral blood, bone marrow, or adipose tissue.
- the disorder is inflammatory lung disease, lung vascular disease, or acute lung injury.
- the inflammatory lung disease is hypoxia-induced lung inflammation, pulmonary hypertension, asthma, bronchopulmonary dysplasia (BPD), allergy, or idiopathic pulmonary fibrosis.
- the acute lung injury is associated with sepsis or is ventilator-induced acute respiratory distress syndrome (ARDS).
- ARDS ventilator-induced acute respiratory distress syndrome
- use of the exosome for the manufacture of medicament for the treatment of a cardiovascular disorder is provided, the disorder being myocardial infarction, cardiovascular disease, hypertension, atherosclerosis, or heart failure.
- the renal disorder is ischemic renal injury, acute renal failure, or renal fibrosis.
- the disorder is hypoxic ischemic encephalopathy or ischemic stroke.
- a method for producing an exosome(s) comprises culturing a cell so as to produce conditioned media and isolating the exosome from the conditioned media.
- the isolated exosome comprises one or more markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105, and/or the isolated exosome does not comprise one or more markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome comprises 2, 3, 4, 5, 6, 7 or 8 markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, the isolated exosome the markers ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, the isolated exosome does not comprise 2, 3, 4, 5, 6 or 7 markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2. In some embodiments, the isolated exosome does not comprise the markers FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the isolated exosome has spherical morphology and appears radiolucent upon negative staining in transmission electron microscopy and/or the isolated exosome does not have a cup shape morphology in negative staining transmission electron microscopy.
- the isolated exosome has a diameter of about 10-150 nm. In some embodiments, the isolated exosome has a diameter of about 30-100 nm.
- the isolated exosome is isolated from a mesenchymal stem cell (MSC), fibroblast, or macrophage.
- the MSC, fibroblast, or macrophage is a human MSC, human fibroblast, or human macrophage.
- the MSC is isolated from Wharton's jelly, umbilical cord blood, placenta, peripheral blood, bone marrow, or adipose tissue.
- the culturing involves two-dimensional (2D) or three-dimensional (3D) culturing.
- the 3D culturing comprises hanging drop culturing, culturing on matrices, culturing on microcarriers, culturing on synthetic extracellular scaffolds, culturing on chitosan membranes, culturing under magnetic levitation, suspension culture in rotating bioreactors, or culturing under non-contact inhibition conditions.
- the culturing comprises use of one or more growth factors selected from TGF ⁇ superfamily (TGF ⁇ 1, Activins, BMPs, GDFs, GDNFs, Inhibins, Nodal, Lefty, MIS) EGF, PDGF, and FGF.
- TGF ⁇ superfamily TGF ⁇ 1, Activins, BMPs, GDFs, GDNFs, Inhibins, Nodal, Lefty, MIS
- EGF EGF
- PDGF PDGF
- FGF FGF ⁇ superfamily
- the method enhances the production of exosomes that comprise one or more markers selected from ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105 relative to exosomes that comprise one or more markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- the enhancement comprises a 1.5-fold, 2.0-fold, 2.5-fold, 3.0-fold, 3.5-fold, 4.0-fold, 4.5-fold, or 5.0-fold, 6.0-fold, 7.0-fold, 8.0-fold, 9.0-fold, or 10.0-fold or more increase in the production of exosomes that comprise one or more markers selected from ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105 relative to exosomes that comprise one or more markers selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2.
- FIGS. 1 A to 1 B Treatment of mice by I.V. injection of mesenchymal stem cell exosome (MEX) preparations down-regulates the hypoxic activation of signaling associated with vascular remodeling & pulmonary hypertension and ameliorates the hypoxia-induced lung inflammation.
- FIG. 1 A Age-matched FVB/n mice were injected with human MEX (20 billion particles/mouse) and exposed to hypoxia for 2.5 days. Hypoxia-induced phosphorylation of AKT and its downstream target mTOR are reduced by MEX treatment. Lung protein levels of the Inhibitor of DNA-binding/differentiation protein ID1, a direct SMAD-targeted gene and downstream signal of BMPR2 are suppressed by hypoxia but increased with MEX. Alpha tubulin serves as normalizing control.
- FIG. 1 B mRNA levels of CCL2, an early inflammatory marker, are suppressed with MEX treatment. RNA levels are normalized to RPS9.
- FIG. 2 Isolation of exosome subpopulations enriched for a-MEX and f-MEX.
- Media conditioned by monolayer cultures of WJ-MSC were concentrated and adjusted to 45% sucrose. This prep was layered on a 60% sucrose cushion and overlayered with a step gradient of 35%-5% sucrose. Preparations were centrifuged for 20 hrs at 180k ⁇ g. The gradient was collected in 14 ⁇ 1 ml fractions. Particle number in each fraction was measured by Nanosight. 20 microL from each fraction were analyzed by Western for the presence of ALIX, FLOT1, CAV1 and SMAD 2/3. Two distinct populations of vesicles were identified with different sedimentation velocities (f-MEX and a-MEX) and different marker composition, based on the above markers.
- FIG. 3 WJ-MSC preparations representing a-MEX and f-MEX were analyzed by western blotting.
- Exosome biogenesis markers such as Alix and Tsg101 are preferentially enriched in a-MEX, while tetraspanins CD9 and CD81 and lipid raft markers, such as flotilin1 and caveolin1 are enriched f-MEX.
- TGFBR2 also specific for a-MEX are TGFBR2 as well as CD105 and members of the SMAD family (not shown here).
- EGF Receptor and members of the AKT family are specific to f-MEX.
- FIG. 4 Negative staining electron microscopy shows differences in size, shape and radiolucency between a-MEX and f-MEX exosome subpopulations. Magnification: 30,000X.
- FIG. 5 FVB/n mice were exposed to hypoxia as in FIGS. 1 A to 1 B and treated with WJ-MSC exosome preparations enriched in either a-MEX or f-MEX. Lungs were harvested after 2.5 days in hypoxia and the mRNA levels of hypoxia-induced inflammatory markers were determined by RT-PCR, using RPS9 as a normalizer. Treatment with a-MEX but not f-MEX results in decrease in mRNA levels of CCL2, IL6 and ADM.
- FIG. 6 A schematic of the process of spheroid formation. Addition of TG ⁇ 3b (10 ng/ml) to monolayer cultures accelerates spheroid formation.
- the insert represents a section of a spheroid of WJ-MSCs stained with toluidine blue.
- FIG. 7 WJ-MSC spheroids predominantly secrete a-MEX.
- WJ-MSCs in standard monolayer culture were trypsinized and the single cell suspension was divided in two equal parts, containing 15 million cells each. One part was propagated in standard media and vessel as a monolayer (2D Culture). The other part was induced into spheroid formation (3D culture) by the hanging drop method (30 spheroids containing 500,000 cells each). An equal volume of clarified media conditioned by the two cultures was assayed for the presence of the indicated markers by Western blotting. Markers specific for a-MEX (SMAD 2/3, ALIX) are enriched in media conditioned by spheroids, and FLOT1, specific for f-MEX is observed predominantly in media conditioned by the monolayer.
- SAD 2/3, ALIX enriched in media conditioned by spheroids
- FLOT1 specific for f-MEX is observed predominantly in media conditioned by the monolayer.
- FIGS. 8 A to 8 B The f-MEX to a-MEX ratio secreted by MSCs from independent donors is inversely correlated with spheroid-forming efficiency.
- WJ-MSCs isolated from two different donors (clone D and Clone C) were cultured under non-adherent conditions (hanging drop technique) for 24 h.
- FIG. 8 A An equal amount of media conditioned by monolayer cultures of each clone was assayed for the a-MEX marker SMAD 2/3 and the f-MEX marker FLOT1 by western blot.
- FIG. 8 B Single cell suspensions of Clone D did not exhibit spheroid forming ability under conditions where identically treated suspensions of Clone C WJ-MSCs were able to form compact spheroids after 24 h as examined by light microscopy. Viability was above 95% after 24 h as assessed by trypan blue. Conditioned media were collected from the hanging drops and exosomes where isolated (as described in Methods). Clone A exosomes were enriched in flotilin1 while clone B in Alix, reflecting differential enrichment of exosome subpopulations in CM.
- FIG. 9 Addition of TGF ⁇ (10 ng/ml) to monolayer cultures of WJ-MSCs accelerates the process of spheroid formation and results in an increase of the ratio of a-MEX markers (such as SMAD2/3) to f-MEX markers (such as FLOT1), indicating an increased proportion of a-MEX in the secreted population.
- a-MEX markers such as SMAD2/3
- f-MEX markers such as FLOT1
- FIGS. 10 A to 10 B a-MEX harbor functional modules of TGF ⁇ signaling.
- FIG. 10 A PBS “C”, TGF ⁇ , FGF or PDGF (10 ng/ml), was added to equal aliquots of a-MEX preparations, followed by incubation at 37 C for 30 min. The preparations were then lysed and subjected to analysis by western blotting. Increased phosphorylation of exosome-associated SMAD 2/3 indicates a functional TGFB2R receptor complex. The effect is not observed by treatment with FGF or PDGF, growth factors not employing the SMAD pathway in their primary signaling.
- FIG. 10 B a-MEX or f-MEX preparations were treated with TGF ⁇ (10 ng/ml) and incubated and analyzed as above. SMAD phosphorylation was specifically observed in a-MEX.
- FIGS. 11 A to 11 C a-MEX but not f-MEX inhibit the TGF ⁇ -induced fibroblast to myofibroblast transition and the LPS-mediated fibroblast activation.
- FIG. 11 A Human lung fibroblasts, after 3 days serum starvation (0.1% FBS), were stimulated with TGF ⁇ to undergo myofibroblast differentiation, marked by increased alpha-smooth muscle actin (SMA) expression. Pretreatment with hMEX (2 ug/ml) abrogates the effect of TGF ⁇ on alpha-SMA protein levels.
- FIG. 11 B Human lung fibroblasts, after 24 h serum starvation were stimulated with TGF ⁇ to induce PAI1, a myofibroblast marker.
- FIG. 11 C a-MEX treatment down regulates baseline MCP-1 and IL1 ⁇ mRNA levels in human lung fibroblasts in vitro.
- the disclosure is based, in part, on the surprising finding that two types of exosomes are derived from cells such as mesenchymal stem cells, and the exosomes can be distinguished based on molecular markers, size, morphology, and function.
- one of the two subpopulations comprises distinct markers and has therapeutic efficacy in the treatment of certain disorders, whereas the other subpopulation comprises a separate and distinct group of markers and lacks therapeutic efficacy in treating certain disorders.
- the disclosure relates broadly to compositions of isolated exosomes and methods of their use in the treatment and/or prevention of certain diseases or disorders including but not limited to lung disorders, cardiovascular disorders, renal disorders, and ischemic neural disorders.
- exosomes of the disclosure are membrane (e.g., lipid bilayer) vesicles that are released from cells such as mesenchymal stem cells (MSCs), fibroblasts, and macrophages.
- MSCs mesenchymal stem cells
- fibroblasts fibroblasts
- macrophages By electron microscopy, exosomes have typically been described as having a cup-shaped morphology.
- aspects of the present disclosure relate to the novel finding that some exosomes (e.g., those having therapeutic efficacy as described herein) within a given preparation display a spherical morphology as opposed to cup-shaped, and are also radiolucent (e.g., translucent) as determined by negative staining transmission electron microscopy.
- Exosomes sediment at about 100,000 ⁇ g and have a buoyant density in sucrose of about 1.10 to about 1.21 g/ml. Exosomes may be referred to as microvesicles or nanovesicles.
- an isolated exosome is one which is physically separated from its natural environment.
- An isolated exosome may be physically separated, in whole or in part, from tissue or cells with which it naturally exists, including MSCs, fibroblasts, and macrophages.
- a composition of isolated exosomes may be free of cells such as MSCs, fibroblasts, and macrophages, or it may be free or substantially free of conditioned media.
- the isolated exosomes are provided at a higher concentration than exosomes present in unmanipulated conditioned media.
- Exosomes may be isolated from conditioned media from cultures of cells including, but not limited to, MSCs, fibroblasts, and macrophages.
- a method for harvest of exosomes from MSCs is provided in the Examples. Briefly, such method involves first culturing MSCs under standard conditions until they reach about 70% confluency, and then culturing the cells in a serum-free media for 24 hours, following which the conditioned media is collected and subjected to differential centrifugation at 400 ⁇ g for 10 minutes and 12000 ⁇ g for 10 minutes in order to remove cells and cellular debris. The clarified conditioned media is then concentrated by ultrafiltration using a 100 kDa MWCO filter (Millipore), and then centrifuged again at 12000 ⁇ g for 10 minutes.
- Exosomes are then isolated using size exclusion chromatography by loading the concentrated conditioned media on a PBS-equilibrated Chroma S-200 column (Clontech), eluting with PBS, and collecting fractions of 350-550 microliters. Fractions containing exosomes are identified and potentially pooled. Protein concentration is measured using a standard Bradford assay (Bio-Rad). Aliquots of the enriched exosome preparations can be stored at ⁇ 80° C.
- Exosomes can also be purified by ultracentrifugation of clarified conditioned media at 100,000 ⁇ g. They can also be purified by ultracentrifugation into a sucrose cushion. GMP methods for exosome purification from dendritic cells have been described in J Immunol Methods. 2002; 270:211-226.
- Exosomes can also be purified by differential filtration, through nylon membrane filters of defined pore size. A first filtration though a large pore size will retain cellular fragments and debris. A subsequent filtration through a smaller pore size will retain exosomes and purify them from smaller size contaminants.
- the exosomes are fractionated into the two subpopulations enriched for certain markers described herein.
- Methods for fractionating the two subpopulations are described in the Examples, and include, for example, velocity ultracentrifugation in step gradients of sucrose (5%-60%), iodixanol (OptiprepTM, 0%-60%) or similar isolation media.
- the disclosure provides two distinct types of exosomes that are distinguished based on molecular markers, size, morphology, and function.
- the two distinct types are referred to as the “a-type” and “f-type” throughout the disclosure, and when derived from MSCs are interchangeably referred to as “a-MEX” (for “a” type MSC derived exosome) or “f-MEX” (for “f” type MSC derived exosome).
- a-MEX for “a” type MSC derived exosome
- f-MEX for “f” type MSC derived exosome
- isolated exosomes of the a-type comprise one or more markers (e.g., proteins) selected from the group consisting of ALIX (also known as “programmed cell death 6 interacting protein” or PDCD6IP; HomoloGene:22614; e.g., NCBI Reference Sequence: NP_001155901.1), TSG101 (tumor susceptibility gene 101; HomoloGene:4584; e.g., NCBI Reference Sequence: NP_006283.1), TGFBR2 (transforming growth factor, beta receptor II; HomoloGene:2435; e.g., NCBI Reference Sequence: NP_001020018.1), SMAD1 (SMAD family member 1; HomoloGene:21196; e.g., NCBI Reference Sequence: NP_001003688.1), SMAD2 (SMAD family member 2; HomoloGene:21197; e.g., NCBI Reference Sequence: NP_
- markers e.g
- the a-type comprises 2, 3, 4, 5, 6, 7, or 8 of these markers.
- an exosome “comprises” a particular marker it is meant that the exosome contains detectable levels (e.g., as determined by Western blotting) of the marker and/or levels sufficient to elicit a certain response in a target cell or tissue or elicit a certain response in a subject in the context of methods of treatment as described herein.
- detectable levels e.g., as determined by Western blotting
- proteins which may be found in a-type exosomes comprise part of the TGF/BMP superfamily of growth factors, which are believed to contribute to their function and therapeutic effects.
- isolated exosomes of the a-type do not comprise one or more markers selected from the group consisting of FLOT1 (flotillin 1; HomoloGene:31337; e.g., NCBI Reference Sequence: NP_005794.1), CD9 (CD9 molecule; HomoloGene:20420; e.g., NCBI Reference Sequence: NP_001760.1), CD81 (CD81 molecule; HomoloGene:20915; e.g., NCBI Reference Sequence: NP_004347.1), CAV1 (caveolin 1; HomoloGene:1330; e.g., NCBI Reference Sequence: NP_001166366.1), EGFR (epidermal growth factor receptor; HomoloGene:74545; e.g., NCBI Reference Sequence: NP_005219.2; NP_958439.1; NP_958440.1; NP_958441.1), AKT1
- the a-type does not comprise 2, 3, 4, 5, 6, or 7 of these markers.
- an exosome “does not comprise” a particular marker it is meant that the exosome contains none of or only insignificant amounts of the particular marker.
- an insignificant amount may be an amount that is undetectable, or an amount that is detectable at only trace amounts.
- an a-type exosome may be distinguished from an f-type exosome based on morphology.
- Exosomes have been typically described as having a cup-shaped morphology.
- the present disclosure provides exosomes (the a-type) having a spherical as opposed to a cup-shaped morphology.
- Methods for assessing exosome morphology are known in the art, and include transmission electron microscopy and negative staining in transmission electron microscopy.
- a-type exosomes were found to be radiolucent (e.g., translucent) using negative staining in transmission electron microscopy.
- the f-type exosomes display cup-shaped morphology and are not radiolucent as determined by negative staining in transmission electron microscopy.
- the a-type exosomes are distinguished from f-type exosomes based on size.
- a-type exosomes have a diameter of about 10-150 nm, about 20-120 nm, or about 30-100 nm.
- isolated exosomes of the f-type comprise one or more markers (e.g., proteins) selected from the group consisting of FLOT1, CD9, CD81, CAV1, EGFR, AKT1 and AKT2. In some embodiments, isolated exosomes of the f-type comprise 2, 3, 4, 5, 6, or 7 of these markers.
- markers e.g., proteins
- an exosome “comprises” a particular marker it is meant that the exosome contains detectable levels (e.g., as determined by Western blotting) of the marker and/or levels sufficient to elicit a certain response in a target cell or tissue or elicit a certain response in a subject in the context of methods of treatment as described herein.
- detectable levels e.g., as determined by Western blotting
- markers e.g., proteins
- the FGF/PDGF signaling pathway is involved in angiogenesis. Accordingly, f-type exosomes (e.g., compositions thereof) are believed to be useful for augmenting angiogenesis.
- isolated f-type exosomes do not comprise one or markers selected from the group consisting of ALIX, TSG101, TGFBR2, SMAD1, SMAD2, SMAD3, SMAD5 and CD105. In some embodiments, f-type exosomes do not comprise 2, 3, 4, 5, 6, 7, or 8 of these markers. In some embodiments, when an exosome “does not comprise” a particular marker, it is meant that the exosome contains none of or only insignificant amounts of the particular marker. For example, an insignificant amount may be an amount that is undetectable, or an amount that is detectable at only trace amounts.
- f-type exosomes display cup-shaped morphology as determined by negative staining transmission electron microscopy.
- f-type exosomes have a diameter of about 10-250 nm, about 20-230 nm, or about 30-200 nm. In some embodiments, f-type exosomes have a diameter of no less than 100 nm.
- Exosomes including both a-type and f-type exosomes, are produced by a number of different cell types, including, but not limited to, MSCs, fibroblasts, and macrophages. Methods for obtaining such cells are well known in the art. Sources of MSCs are described in more detail herein.
- the disclosure also contemplates the use of synthetic exosomes having some or all the characteristics of the isolated exosomes described herein.
- These synthetic exosomes would be synthesized in vitro (rather than derived and isolated from cells or conditioned media). They may be synthetic liposomes having one or more, including 2, 3, 4, 5, 6, 7, 8 or more of the proteins provided herein. They may or may not comprise nucleic acids that encode one or more, including 2, 3, 4, 5, 6, 7, 8 or more of these proteins. Liposome synthesis is known in the art, and liposomes may be purchased from commercial sources.
- compositions, formulations, methods and uses described herein relating to exosomes derived and isolated from cells (or conditioned media from cells) such as MSCs, fibroblasts, or macrophages are also contemplated in the context of synthetic exosomes.
- the disclosure contemplates immediate use of exosomes or alternatively short- and/or long-term storage of exosomes, for example, in a cryopreserved state prior to use.
- Proteinase inhibitors are typically included in freezing media as they provide exosome integrity during long-term storage. Freezing at ⁇ 20° C. is not preferable since it is associated with increased loss of exosome activity. Quick freezing at ⁇ 80° C. is more preferred as it preserves activity. (See for example Kidney International (2006) 69, 1471-1476.)
- Additives to the freezing media may be used in order to enhance preservation of exosome biological activity. Such additives will be similar to the ones used for cryopreservation of intact cells and may include, but are not limited to DMSO, glycerol and polyethylene glycol.
- a mesenchymal stem cell is a progenitor cell having the capacity to differentiate into neuronal cells, adipocytes, chondrocytes, osteoblasts, myocytes, cardiac tissue, and other endothelial and epithelial cells.
- MSC mesenchymal stem cell
- MSCs may be characterized phenotypically and/or functionally according to their differentiative potential.
- MSCs may be harvested from a number of sources including but not limited to bone marrow, blood, periosteum, dermis, umbilical cord blood and/or matrix (e.g., Wharton's Jelly), and placenta. Methods for harvest of MSCs are described in greater detail in the Examples. Reference can also be made to U.S. Pat. No. 5,486,359 for other harvest methods that can be used in the present disclosure.
- a fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework (e.g., stroma) for animal tissues, and plays a critical role in wound healing.
- Fibroblasts are the most common cells of connective tissue in animals. Fibroblasts typically have a branched cytoplasm surrounding an elliptical, speckled nucleus having two or more nucleoli. Active fibroblasts can be recognized by their abundant rough endoplasmic reticulum. Inactive fibroblasts, which are also called fibrocytes, are smaller and spindle shaped. They have a reduced rough endoplasmic reticulum.
- Sources of fibroblasts include connective tissues such as loose, dense, elastic, reticular, and adipose connective tissue.
- connective tissues such as loose, dense, elastic, reticular, and adipose connective tissue.
- embryonic connective tissues as well as specialized connective tissues, which include bone, cartilage, and blood.
- Other sources include the skin.
- Methods for isolating and culturing fibroblasts are well known in the art (See, e.g., Weber et al., “Isolation and Culture of Fibroblasts, Vascular Smooth Muscle, and Endothelial Cells From the Fetal Rat Ductus Arteriosus.” Pediatric Research. 2011; 70, 236-241; Huschtscha et al., “Enhanced isolation of fibroblasts from human skin explants.” Biotechniques. 2012; 53(4):239-44; the entire contents of which are hereby incorporated by reference).
- fibroblasts are used for the production and isolation of exosomes as described herein.
- Methods for producing and isolating exosomes from fibroblasts are known in the art (See, e.g., Luga et al., “Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration.” Cell. 2012; 151(7):1542-56; Bang et al., “Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy.” J Clin Invest. 2014; 124(5):2136-46; Hoffman, “Stromal-cell and cancer-cell exosomes leading the metastatic exodus for the promised niche.” Breast Cancer Research, 2013; 15:310; the entire contents of each are hereby incorporated by reference.)
- a macrophage is a cell produced by the differentiation of monocytes in tissues. Macrophages function in both non-specific defense (innate immunity) as well as help initiate specific defense mechanisms (adaptive immunity) of vertebrate animals. They are specialized phagocytic cells that attack foreign substances, infectious microbes and cancer cells through destruction and ingestion. They are present in all living tissues, and have a function in regeneration. Macrophages can be identified by specific expression of a number of proteins including CD14, CD40, CD11b, CD64, F4/80 (mice)/EMR1 (human), lysozyme M, MAC-1/MAC-3 and CD68 by flow cytometry, immunohistochemical staining, or other suitable methods.
- innate immunity non-specific defense
- adaptive immunity adaptive immunity
- Sources of macrophages include nearly any tissue, and are readily sourced from blood and bone marrow.
- Methods of isolating and culturing macrophages are well known in the art (See, e.g., Bennet, “Isolation and cultivation in vitro of macrophages from various sources in the mouse.” Am J Pathol. January 1966; 48(1): 165-181; Davies and Gordon, “Isolation and culture of murine macrophages.” Methods Mol Biol. 2005; 290:91-103; Weischenfeldt and Porse, “Bone Marrow-Derived Macrophages (BMM): Isolation and Applications.” CSH Protoc. 2008:pdb.prot5080. doi: 10.1101/pdb.prot5080; the entire contents of each are hereby incorporated by reference.)
- macrophages or macrophage conditioned media, are used for the production and isolation of exosomes as described herein.
- Methods for producing and isolating exosomes from macrophages are known in the art (See, e.g., Lee et al., “Exosomes derived from human macrophages suppress endothelial cell migration by controlling integrin trafficking.” Eur J Immunol. 2014; 44(4):1156-69; Yang et al., “Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells.” Mol Cancer.
- the MSCs, fibroblasts, and/or macrophages, and thus the exosomes derived therefrom, contemplated for use in the methods of the disclosure may be derived from the same subject to be treated (and therefore would be referred to as autologous to the subject) or they may be derived from a different subject preferably of the same species (and therefore would be referred to as allogeneic to the subject).
- an isolated cell e.g., MSC, fibroblast, and/or macrophage
- MSC a cell that has been physically separated from its natural environment, including physical separation from one or more components of its natural environment.
- an isolated cell or cell population embraces a cell or a cell population that has been manipulated in vitro or ex vivo.
- isolated cells e.g., MSCs, fibroblasts, and/or macrophages
- the isolated cells are present in a population that is at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% cells as phenotypically and/or functionally defined herein.
- the ratio of MSCs, fibroblasts and/or macrophages to other cells is increased in the isolated preparation as compared to the starting population of cells.
- MSCs can be isolated using methods known in the art, e.g., from bone marrow mononuclear cells, umbilical cord blood, adipose tissue, placental tissue, based on their adherence to tissue culture plastic.
- MSCs can be isolated from commercially available bone marrow aspirates. Enrichment of MSCs within a population of cells can be achieved using methods known in the art including but not limited to FACS.
- DMEM Dulbecco's modified Eagle's medium
- Components in such media that are useful for the growth, culture and maintenance of MSCs, fibroblasts, and macrophages include but are not limited to amino acids, vitamins, a carbon source (natural and non-natural), salts, sugars, plant derived hydrolysates, sodium pyruvate, surfactants, ammonia, lipids, hormones or growth factors, buffers, non-natural amino acids, sugar precursors, indicators, nucleosides and/or nucleotides, butyrate or organics, DMSO, animal derived products, gene inducers, non-natural sugars, regulators of intracellular pH, betaine or osmoprotectant, trace elements, minerals, non-natural vitamins.
- DMEM Dulbecco's modified Eagle's medium
- tissue culture medium e.g., animal serum (e.g., fetal bovine serum (FBS), fetal calf serum (FCS), horse serum (HS)), antibiotics (e.g., including but not limited to, penicillin, streptomycin, neomycin sulfate, amphotericin B, blasticidin, chloramphenicol, amoxicillin, bacitracin, bleomycin, cephalosporin, chlortetracycline, zeocin, and puromycin), and glutamine (e.g., L-glutamine).
- FBS fetal bovine serum
- FCS fetal calf serum
- HS horse serum
- antibiotics e.g., including but not limited to, penicillin, streptomycin, neomycin sulfate, amphotericin B, blasticidin, chloramphenicol, amoxicillin, bacitracin, bleomycin, cephalosporin, chlortetra
- culture conditions can bias the production of exosome type.
- the culture conditions can bias the production of a-type exosomes versus f-type exosomes.
- three-dimensional (3D) culturing enhances the production of a-type exosomes over f-type exosomes, as compared to traditional two-dimensional (e.g., monolayer) culturing.
- Methods for 3D culture are well known in the art, and include, but are not limited to hanging drop culture, culturing on matrices, culturing on microcarriers, culturing on synthetic extracellular scaffolds, culturing on chitosan membranes, culturing under magnetic levitation, suspension culture in rotating bioreactors, or culturing under non-contact inhibition conditions. See, e.g., Haycock J W. (2011). “3D cell culture: a review of current approaches and techniques.”. Methods Mol Biol. 695: 1-15; Lee, J; Cuddihy M J, Kotov N A. (14 Mar. 2008). Three - dimensional cell culture matrices: state of the art .
- TGF ⁇ superfamily TGF ⁇ 1, Activins, BMPs, GDFs, GDNFs, Inhibins, Nodal, Lefty, MIS
- EGF EGF
- PDGF PDGF
- FGF FGF
- the enhancement (e.g., in the context of 3D culturing and/or growth factor addition) comprises a 1.1-fold, a 1.2-fold, a 1.3-fold, a 1.5-fold, a 1.6-fold, a 1.7-fold, a 1.8-fold, a 1.9-fold, a 2.0-fold, a 2.5-fold, a 3.0-fold, a 3.5-fold, a 4.0-fold, a 4.5-fold, a 5.0-fold, a 5.5-fold, a 6.0-fold, a 6.5-fold, a 7.0-fold, a 7.5-fold, a 8.5-fold, a 9.0-fold, a 9.5-fold, a 10.0-fold, a 12.0-fold, a 15.0-fold, or a 20.0-fold or more increase of a-type exosomes relative to f-type exosomes.
- the methods of the disclosure may be performed on any subject likely to derive benefit therefrom, including human subjects, agricultural livestock (e.g., cows, pigs, etc.), prized animals (e.g., horses), companion animals (e.g., dogs, cats, etc.), and the like.
- human subjects are preferred.
- human subjects and human MSC exosomes are used.
- the subjects may be those that have a disease (or condition) described herein amenable to treatment using the exosomes described in this disclosure, or they may be those that are at risk of developing such a disease (or condition).
- Such subjects include neonates and particularly neonates born at low gestational age.
- a human neonate refers to an human from the time of birth to about 4 weeks of age.
- a human infant refers to a human from about the age of 4 weeks of age to about 3 years of age.
- low gestational age refers to birth (or delivery) that occurs before a normal gestational term for a given species. In humans, a full gestational term is about 40 weeks and may range from 37 weeks to more than 40 weeks.
- Low gestational age, in humans, akin to a premature birth is defined as birth that occurs before 37 weeks of gestation.
- the disclosure therefore contemplates prevention and/or treatment of subjects born before 37 weeks of gestation, including those born at even shorter gestational terms (e.g., before 36, before 35, before 34, before 33, before 32, before 31, before 30, before 29, before 28, before 27, before 26, or before 25 weeks of gestation).
- premature infants will be treated as neonates, however the disclosure contemplates their treatment even beyond the neonate stage and into childhood and/or adulthood.
- Certain subjects may have a genetic predisposition to certain forms of the diseases (or conditions) described herein such as for example pulmonary hypertension, and those subjects may also be treated according to the disclosure.
- exosomes of the a-type comprise functional signaling components of the TGF/BMP pathway, and are therapeutically effective in the treatment of disorders involving this pathway.
- disorders include certain lung and vascular disorders, as described herein (See, e.g., Cai et al., “BMP signaling in vascular diseases” FEBS Lett.
- mice by I.V. injection of a-type exosome preparations down-regulated the hypoxic activation of signaling associated with vascular remodeling and pulmonary hypertension and ameliorated the hypoxia-induced lung inflammation.
- aspects of the disclosure provide compositions and methods to prevent and/or treat a number of lung (or pulmonary) diseases.
- diseases include inflammatory lung diseases such as but not limited to pulmonary hypertension (PH) which is also referred to as pulmonary artery hypertension (PAH), asthma, bronchopulmonary dysplasia (BPD), allergies, sarcoidosis, and idiopathic pulmonary fibrosis.
- PH pulmonary hypertension
- PAH pulmonary artery hypertension
- BPD bronchopulmonary dysplasia
- allergies sarcoidosis
- idiopathic pulmonary fibrosis idiopathic pulmonary fibrosis.
- diseases also include lung vascular diseases which may not have an inflammatory component.
- Still other pulmonary conditions that may be treated according to the disclosure include acute lung injury which may be associated with sepsis or with ventilation. An example of this latter condition is acute respiratory distress syndrome which occurs in older children and adults.
- Pulmonary hypertension is a lung disease characterized by blood pressure in the pulmonary artery that is far above normal levels. Symptoms include shortness of breath, chest pain particularly during physical activity, weakness, fatigue, fainting, light headedness particularly during exercise, dizziness, abnormal heart sounds and murmurs, engorgement of the jugular vein, retention of fluid in the abdomen, legs and ankles, and bluish coloring in the nail bed.
- Bronchopulmonary dysplasia is a condition that afflicts neonates who have been given oxygen or have been on ventilators, or neonates born prematurely particularly those born very prematurely (e.g., those born before 32 weeks of gestation). It is also referred to as neonatal chronic lung disease.
- causes of BPD include mechanical injury for example as a result of ventilation, oxygen toxicity for example as a result of oxygen therapy, and infection.
- the disease may progress from non-inflammatory to inflammatory with time. Symptoms include bluish skin, chronic cough, rapid breathing, and shortness of breath.
- Subjects having BPD are more susceptible to infections such as respiratory syncytial virus infection.
- Subjects having BPD may develop pulmonary hypertension.
- ARDS Acute respiratory distress syndrome
- RDS respiratory distress syndrome
- adult respiratory distress syndrome is a condition that arises as a result of injury to the lungs or acute illness.
- the injury to the lung may be a result of ventilation, trauma, burns, and/or aspiration.
- the acute illness may be infectious pneumonia or sepsis. It is considered a severe form of acute lung injury, and it is often fatal. It is characterized by lung inflammation, impaired gas exchange, and release of inflammatory mediators, hypoxemia, and multiple organ failure.
- ARDS can also be defined as the ratio of arterial partial oxygen tension (PaO 2 ) as a fraction of inspired oxygen (FiO 2 ) below 200 mmHg in the presence of bilateral infiltrates on the chest x-ray.
- PaO 2 arterial partial oxygen tension
- FiO 2 inspired oxygen
- a PaO 2 /FiO 2 ratio less than 300 mmHg with bilateral infiltrates indicates acute lung injury, which is often a precursor to ARDS.
- Symptoms of ARDS include shortness of breath, tachypnea, and mental confusion due to low oxygen levels.
- Idiopathic pulmonary fibrosis is characterized by scarring or thickening of the lungs without a known cause. It occurs most often in persons 50-70 years of age. Its symptoms include shortness of breath, regular cough (typically a dry cough), chest pain, and decreased activity level.
- Allergy is a hypersensitivity disorder of the immune system, with symptoms including red eyes, itchiness, and runny nose, eczema, hives, or an asthma attack. Allergies play a major role in conditions such as asthma. Severe allergies to environmental or dietary allergens or to medication may result in life-threatening reactions called anaphylaxis. Allergic reactions can occur when a person's immune system reacts to what is often a normally harmless substance in the environment. Allergy is one of four forms of hypersensitivity and is sometimes called type I (or immediate) hypersensitivity. Allergic reactions are distinctive because of excessive activation of certain white blood cells (mast cells and basophils) by Immunoglobulin E (IgE). This reaction results in an inflammatory response which can range from mild discomfort to dangerous. A variety of tests exist to diagnose allergic conditions. Tests include placing possible allergens on the skin and looking for a reaction such as swelling and blood tests to look for an allergen-specific IgE.
- Hypoxia-induced lung inflammation is a condition often resulting from acute lung injury and/or ARDS, whereby an inflammatory response results from prolonged exposure to hypoxic conditions.
- Such inflammatory response includes increased macrophages, neutrophils, and inflammatory cytokines, including IL-1 ⁇ , IL-6, IL-8, and TNF- ⁇ , in the bronchoalveolar lavage fluid of humans exposed to hypobaric hypoxia.
- cardiovascular disorders for example myocardial infarction, cardiovascular disease, hypertension, atherosclerosis, and heart failure (See, e.g., Pardali et al., “TGF ⁇ Signaling and Cardiovascular Diseases.” Int J Biol Sci 2012; 8(2):195-213; Garside et al., “Coordinating Notch, BMP, and TGF- ⁇ signaling during heart valve development.” Cell Mol Life Sci.
- Myocardial infarction is the medical term for an event commonly known as a heart attack.
- Myocardial infarction occurs when blood stops flowing properly to part of the heart and the heart muscle is injured due to not receiving enough oxygen. This is usually caused when one of the coronary arteries that supplies blood to the heart develops a blockage due to an unstable buildup of white blood cells, cholesterol and fat. The event is called “acute” if it is sudden and serious.
- Symptoms of an acute myocardial infarction include sudden chest pain that is felt behind the breast bone and sometimes travels to the left arm or the left side of the neck. Additionally, the individual may have shortness of breath, sweating, nausea, vomiting, abnormal heartbeats, and anxiety. Women experience fewer of these symptoms than men, but usually have shortness of breath, weakness, a feeling of indigestion, and fatigue.
- Cardiovascular disease refers to any disease that affects the cardiovascular system, principally cardiac disease, vascular diseases of the brain and kidney, and peripheral arterial disease.
- the causes of cardiovascular disease are diverse but atherosclerosis and/or hypertension are the most common.
- atherosclerosis and/or hypertension are the most common.
- with aging come a number of physiological and morphological changes that alter cardiovascular function and lead to increased risk of cardiovascular disease, even in healthy asymptomatic individuals.
- Atherosclerosis is a specific form of arteriosclerosis in which an artery wall thickens as a result of invasion and accumulation of white blood cells and containing both living active WBCs (inflammation) and remnants of dead cells, including cholesterol and triglycerides, eventually calcium and other crystallized materials, within the outer-most and oldest plaque.
- Symptoms can result from a marked narrowing in the coronary arteries, which are responsible for bringing oxygenated blood to the heart, producing symptoms such as the chest pain of angina and shortness of breath, sweating, nausea, dizziness or light-headedness, breathlessness or palpitations. Marked narrowing of the carotid arteries can also present with symptoms such as a feeling of weakness, not being able to think straight, difficulty speaking, becoming dizzy and difficulty in walking or standing up straight, blurred vision, numbness of the face, arms, and legs, severe headache and losing consciousness. These symptoms are also related to stroke i.e., death of brain cells.
- Stroke is caused by marked narrowing/closure of arteries going to the brain; lack of adequate of blood supply leads to the death of the cells of the affected tissue.
- Peripheral arteries which supply blood to the legs, arms, and pelvis, also experience marked narrowing due to plaque rupture and clots. Symptoms for the marked narrowing are numbness within the arms or legs, as well as pain.
- Another significant location for the plaque formation are the renal arteries, which would supply blood to the kidneys. Plaque occurrence and accumulation leads to decreased kidney blood flow and chronic kidney disease, which, like all other areas, are typically asymptomatic until late stages.
- Hypertension or high blood pressure is a chronic medical condition in which the blood pressure in the arteries is elevated. Hypertension is classified as either primary (essential) hypertension or secondary hypertension; about 90-95% of cases are categorized as “primary hypertension” which means high blood pressure with no obvious underlying medical cause. The remaining 5-10% of cases (secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart or endocrine system. Hypertension puts strain on the heart, leading to hypertensive heart disease and coronary artery disease if not treated. Hypertension is also a major risk factor for stroke, aneurysms of the arteries (e.g. aortic aneurysm), peripheral arterial disease and is a cause of chronic kidney disease.
- aneurysms of the arteries e.g. aortic aneurysm
- peripheral arterial disease is a cause of chronic kidney disease.
- Hypertension is rarely accompanied by any symptoms, and its identification is usually through screening, or when seeking healthcare for an unrelated problem.
- a proportion of people with high blood pressure report headaches (particularly at the back of the head and in the morning), as well as lightheadedness, vertigo, tinnitus (buzzing or hissing in the ears), altered vision or fainting episodes.
- Heart failure often used to mean chronic heart failure, occurs when the heart is unable to provide sufficient pump action to maintain blood flow to meet the needs of the body. When edema is present in addition to the above it is called congestive heart failure (CHF) or congestive cardiac failure (CCF). Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. Common causes of heart failure include myocardial infarction (heart attack) and other forms of coronary artery disease, hypertension, valvular heart disease, and cardiomyopathy. The term heart failure is sometimes incorrectly used for myocardial infarction (which may cause heart failure, but is not heart failure in itself) or for cardiac arrest (in which blood flow effectively stops altogether).
- CHF congestive heart failure
- CCF congestive cardiac failure
- Still other disorders which are amenable to treatment using the a-type exosomes, e.g., by augmenting the TGF/BMP pathway include renal disorders, for example ischemic renal injury, acute renal failure, and renal fibrosis (See, e.g., Meng et al., “Role of the TGF- ⁇ /BMP-7/Smad pathways in renal diseases.” Clin Sci ( Lond ). 2013; 124(4):243-54; Zerisberg et al., “BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.” Nat Med.
- Ischemic renal injury or ischemic nephropathy occurs when there is inadequate blood flow (hypoperfusion) to the kidneys. Hypoperfusion can results in loss of kidney function and kidney atrophy (shrinkage). Renal failure results when this process damages both kidneys.
- RAS renal artery stenosis
- unilateral RAS in a person who has only one functioning kidney
- ischemic renal injury Symptoms of ischemic renal injury include uremia (high blood levels of protein by-products, such as urea); acute episodes of dyspnea (labored or difficult breathing) caused by sudden accumulation of fluid in the lungs; and hypertension may be present, depending on the severity of the injury.
- bruits sound or murmurs heard with a stethoscope
- turbulent blood flow within the arteries may be detected in the neck (carotid artery bruit), abdomen (which may reflect narrowing of the renal artery), and groin (femoral artery bruit).
- Acute renal failure or acute kidney injury is an abrupt loss of kidney function that typically develops within 7 days. It generally occurs as a result of damage to the kidney tissue caused by decreased renal blood flow (renal ischemia) from any cause (e.g. low blood pressure), exposure to substances harmful to the kidney, an inflammatory process in the kidney, or an obstruction of the urinary tract which impedes the flow of urine.
- Acute renal failure is diagnosed on the basis of characteristic laboratory findings, such as elevated blood urea nitrogen and creatinine, or inability of the kidneys to produce sufficient amounts of urine. Acute renal failure may lead to a number of complications, including metabolic acidosis, high potassium levels, uremia, changes in body fluid balance, and effects to other organ systems.
- Symptoms of acute kidney injury include accumulation of urea and other nitrogen-containing substances in the bloodstream lead to a number of symptoms, such as fatigue, loss of appetite, headache, nausea and vomiting. Increases in the potassium level can lead to irregularities in the heartbeat, which can be severe and life-threatening. Fluid balance is often affected, though hypertension is rare. Pain in the flanks is encountered in some conditions (e.g., thrombosis of the renal blood vessels or inflammation of the kidney); this is the result of stretching of the fibrous tissue capsule surrounding the kidney. If the kidney injury is the result of dehydration, there may be thirst as well as evidence of fluid depletion on physical examination.
- Physical examination may also provide other clues as to the underlying cause of the kidney problem, such as a rash in interstitial nephritis and a palpable bladder. Decreased ability to excrete sufficient fluid from the body can cause accumulation of fluid in the limbs (peripheral edema) and the lungs (pulmonary edema), as well as cardiac tamponade as a result of fluid effusions.
- Renal fibrosis results from an excessive accumulation of extracellular matrix that occurs in virtually every type of chronic kidney disease.
- the pathogenesis of renal fibrosis is a progressive process that typically leads to end-stage renal failure.
- renal fibrosis represents a failed wound-healing process of the kidney tissue after chronic, sustained injury.
- Many cellular pathways e.g., mesangial and fibroblast activation as well as tubular epithelial-mesenchymal transition, have been identified as the major causes for the generation of the matrix-producing cells in diseased conditions.
- Fibrogenic factors that regulate renal fibrotic process such as transforming growth factor (TGF), contribute to the condition.
- TGF transforming growth factor
- ischemic neural disorders such as hypoxic ischemic encephalopathy or ischemic stroke
- ischemic neural disorders such as hypoxic ischemic encephalopathy or ischemic stroke
- Harvey et al. “Stroke and TGF-beta proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein.” Pharmacol Ther. 2005; 105(2):113-25; Krampert et al., “Smad7 regulates the adult neural stem/progenitor cell pool in a transforming growth factor beta- and bone morphogenetic protein-independent manner.” Mol Cell Biol.
- Hypoxic ischemic encephalopathy or perinatal asphyxia, is characterized by clinical and laboratory evidence of acute or sub-acute brain injury due to asphyxia. The primary causes of this condition are systemic hypoxemia and/or reduced cerebral blood flow. birth asphyxia causes 840,000 or 23% of all neonatal deaths worldwide. Signs and symptoms of mild hypoxic-ischemic encephalopathy include: muscle tone being slightly increased; and transient behavioral abnormalities (such as poor feeding, irritability, or excessive crying or sleepiness) may be observed.
- Symptoms of moderately severe hypoxic-ischemic encephalopathy include: the infant being lethargic, with significant hypotonia and diminished deep tendon reflexes; the grasping, Moro, and sucking reflexes may be sluggish or absent; the infant may experience occasional periods of apnea; and seizures may occur early within the first 24 hours after birth.
- Symptoms of severe hypoxic-ischemic encephalopathy include seizures which are delayed and severe and which may be initially resistant to conventional treatments. The seizures are usually generalized, and their frequency may increase during the 24-48 hours after onset, correlating with a phase of reperfusion injury.
- Other symptoms include: stupor or coma (the infant may not respond to any physical stimulus except the most noxious); irregular breathing; generalized hypotonia and depressed deep tendon reflexes; absent neonatal reflexes (e.g., sucking, swallowing, grasping, Moro); disturbances of ocular motion (e.g., a skewed deviation of the eyes, nystagmus, bobbing); dilated pupils, fixed, or poorly reactive to light; and irregularities of heart rate and blood pressure.
- Ischemic stroke is the loss of brain function due to a disturbance in the blood supply to the brain. Ischemia is caused by either blockage of a blood vessel via thrombosis or arterial embolism, or by cerebral hypoperfusion. As a result, the affected area of the brain cannot function normally, which might result in an inability to move one or more limbs on one side of the body, failure to understand or formulate speech, or a vision impairment of one side of the visual field.
- Prevention and/or treatment may involve in some instances use of the a-type exosomes alone or together with one or more secondary agents.
- Subjects may also be subjected to mechanical interventions such as ventilation with or without exogenous oxygen administration.
- the disclosure contemplates administration of a-type exosomes within 4 weeks, 3 weeks, 2 weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 12 hours, 6 hours, 3 hours, or 1 hour of birth.
- the a-type exosomes are administered within 1 hour of birth.
- the disclosure further contemplates administration of a-type exosomes even in the absence of symptoms indicative of a disease or disorder as described herein.
- the disclosure also contemplates repeated administration of a-type exosomes, including two, three, four, five or more administrations of a-type exosomes.
- the a-type exosomes may be administered continuously. Repeated or continuous administration may occur over a period of several hours (e.g., 1-2, 1-3, 1-6, 1-12, 1-18, or 1-24 hours), several days (e.g., 1-2, 1-3, 1-4, 1-5, 1-6 days, or 1-7 days) or several weeks (e.g., 1-2 weeks, 1-3 weeks, or 1-4 weeks) depending on the severity of the condition being treated.
- the time in between administrations may be hours (e.g., 4 hours, 6 hours, or 12 hours), days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days), or weeks (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks).
- the time between administrations may be the same or they may differ.
- the symptoms of the disease appear to be worsening the a-type exosomes may be administered more frequently, and then once the symptoms are stabilized or diminishing the a-type exosomes may be administered less frequently.
- the a-type exosomes are administered at least once within 24 hours of birth and then at least once more within 1 week of birth. Even more preferably, the a-type exosomes are administered at least once within 1 hour of birth and then at least once more within 3-4 days of birth.
- repeated intravenous administration of low doses of a-type exosomes may occur. Accordingly, the disclosure contemplates repeated administration of low dosage forms of a-type exosomes as well as single administrations of high dosage forms of a-type exosomes. Low dosage forms may range from, without limitation, 1-50 micrograms per kilogram, while high dosage forms may range from, without limitation, 51-1000 micrograms per kilogram. It will be understood that, depending on the severity of the disease, the health of the subject, and the route of administration, inter alia, the single or repeated administration of low or high dose a-type exosomes are contemplated by the disclosure.
- the a-type exosomes may be used (e.g., administered) in pharmaceutically acceptable preparations (or pharmaceutically acceptable compositions), typically when combined with a pharmaceutically acceptable carrier.
- pharmaceutically acceptable preparations typically when combined with a pharmaceutically acceptable carrier.
- Such preparations may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, and may optionally comprise other (i.e., secondary) therapeutic agents.
- a pharmaceutically acceptable carrier is a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a prophylactically or therapeutically active agent.
- a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a prophylactically or therapeutically active agent.
- Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
- materials which can serve as pharmaceutically acceptable carriers include sugars, such as lactose, glucose and sucrose; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; buffering agents, such as magnesium hydroxide and aluminum hydroxide; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.
- sugars such as lactose, glucose and sucrose
- glycols such as propylene glycol
- polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
- esters such as ethyl oleate and ethyl laurate
- buffering agents such as magnesium hydroxide and aluminum hydroxide
- the exosomes may be administered with one or more secondary therapeutic agents.
- a therapeutic agent refers to any agent which can be used in the prevention, treatment and/or management of a lung disease such as those discussed herein. These include but are not limited to surfactants, inhaled nitric oxide, almitrine bismesylate, immunomodulators, and antioxidants. Examples of immunomodulators include steroids and corticosteroids such as but not limited to methylprednisolone. Examples of antioxidants include but are not limited to superoxide dismutase.
- Certain secondary therapeutic agents used in the treatment or management of certain lung and vascular diseases including but not limited to pulmonary hypertension include oxygen, anticoagulants such as warfarin (Coumadin); diuretics such as furosemide (Lasix®) or spironalactone (Aldactone®); calcium channel blockers; potassium such as Kdur®; inotropic agents such as digoxin; vasodilators such as nifedipine (Procardia®) or diltiazem (Cardizem®); endothelin receptor antagonists such as bosentan (Tracleer®) and ambrisentan (Letairis®); prostacyclin analogues such as epoprostenol (Flolan®), treprostinil sodium (Remodulin®, Tyvaso®), and iloprost (Ventavis®); and PDE-5 inhibitors such as sildenafil (Revatio®) and tadalafil (Adcirca®).
- the a-type exosomes may be administered with pulmonary surfactants.
- a pulmonary surfactant is a lipoprotein mixture useful in keeping lung airways open (e.g., by preventing adhesion of alveolar walls to each other).
- Pulmonary surfactants may be comprised of phospholipids such as dipalmitoylphosphatidylcholine (DPPC), phosphotidylcholine (PC), phosphotidylglycerol (PG); cholesterol; and proteins such as SP-A, B, C and D.
- Pulmonary surfactants may be derived from naturally occurring sources such as bovine or porcine lung tissue.
- Pulmonary surfactants may also be synthetic.
- ExosurfTM (comprised of DPPC with hexadecanol and tyloxapol), PumactantTM or Artificial Lung Expanding Compound (ALEC) (comprised of DPPC and PG), KL-4 (comprised of DPPC, palmitoyl-oleoyl phosphatidylglyercol, palmitic acid, and synthetic peptide that mimics SP-B), VenticuteTM (comprised of DPPC, PG, palmitic acid, and recombinant SP-C).
- Pulmonary surfactants may be obtained from commercial suppliers.
- the preparations of the disclosure are administered in effective amounts.
- An effective amount is that amount of an agent that alone stimulates the desired outcome.
- the absolute amount will depend upon a variety of factors, including the material selected for administration, whether the administration is in single or multiple doses, and individual patient parameters including age, physical condition, size, weight, and the stage of the disease. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation.
- the a-type exosomes may be administered by any route that effects delivery to the lungs or other tissues.
- Systemic administration routes such as intravenous bolus injection or continuous infusion are suitable. More direct routes such as intranasal administration, intratracheal administration (e.g., via intubation), and inhalation (e.g., via an aerosol through the mouth or nose) are also contemplated by the disclosure and in some instances may be more appropriate particularly where rapid action is necessary.
- an aerosol is a suspension of liquid dispersed as small particles in a gas, and it includes a fine mist or a spray containing such particles.
- aerosolization is the process of producing of an aerosol by transforming a liquid suspension into small particles or droplets.
- Nebulizers include air-jet (i.e., pneumatic), ultrasonic, and vibrating-mesh nebulizers, for example with the use of a suitable propellant such as but not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- a suitable propellant such as but not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- other devices for pulmonary delivery include but are not limited to metered dose inhalers (MDIs) and dry powder inhalers (DPIs).
- MDIs metered dose inhalers
- DPIs dry powder inhalers
- Capsules and cartridges of for example gelatin for use in an inhaler or insufflator may be formulated containing lyophilized exosomes and a suitable powder base such
- exosomes when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, including for example by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with or without an added preservative.
- compositions may take such forms as water-soluble suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides.
- Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
- the suspension may also contain suitable stabilizers or agents which increase solubility.
- the exosomes may be in lyophilized or other powder or solid form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
- agents to be administered to subjects being treated according to the disclosure may be administered by any suitable route including oral administration, intranasal administration, intratracheal administration, inhalation, intravenous administration, etc.
- suitable route including oral administration, intranasal administration, intratracheal administration, inhalation, intravenous administration, etc.
- Those of ordinary skill in the art will know the customary routes of administration for such secondary agents.
- the disclosure also encompasses a packaged and labelled pharmaceutical product.
- This article of manufacture or kit includes the appropriate unit dosage form in an appropriate vessel or container such as a glass vial or plastic ampoule or other container that is hermetically sealed.
- the unit dosage form should be suitable for pulmonary delivery for example by aerosol.
- the article of manufacture or kit further comprises instructions on how to use including how to administer the pharmaceutical product.
- the instructions may further contain informational material that advises a medical practitioner, technician or subject on how to appropriately prevent or treat the disease or disorder in question.
- the article of manufacture includes instructions indicating or suggesting a dosing regimen for use including but not limited to actual doses, monitoring procedures, and other monitoring information.
- the packaging material and container are designed to protect the stability of the product during storage and shipment.
- kits may include exosomes in sterile aqueous suspensions that may be used directly or may be diluted with normal saline for intravenous injection or use in a nebulizer, or dilution or combination with surfactant for intratracheal administration.
- the kits may therefore also contain the diluent solution or agent, such as saline or surfactant.
- the kit may also include a pulmonary delivery device such as a nebulizer or disposable components therefore such as the mouthpiece, nosepiece, or mask.
- hUC-MSCs Human umbilical cord Wharton's jelly derived MSCs (hUC-MSCs) were isolated according to published methods (Mitchell, K. E. et al., 2003, Stem Cells 21:50-60; and Penolazzi, L. et al., 2011 , J Cell Physiol ) with minor modifications. Cord was rinsed twice with cold sterile PBS, cut longitudinally, and arteries and vein were removed.
- the soft gel tissues were scraped out, finely chopped (2-3 mm 2 ) and directly placed on 100 mm dishes (15 pieces per dish) with DMEM/F12 (1:1) (Invitrogen) supplemented with 10% fetal bovine serum (Hyclone), 2 mM L-glutamine, and penicillin/streptomycin, and incubated for 5 days at 37° C. in a humidified atmosphere of 5% CO 2 . After removal of tissue and medium, the plates were washed 3 times with PBS, the attached cells were cultured and fresh media replaced 3 times per week. At 70-80% confluence, cells were collected and stained with PE conjugated antibodies for CD34 (Miltenybiotec) and CD45 (Miltenybiotec).
- Immunodepletion was performed using the anti-PE-microbeads (Miltenybiotec) and MSCS column (Miltenybiotec) according to manufacturer's instructions.
- the CD34 and CD45 negative populations were further propagated and selected for the expression of MSC markers (CD105, CD90, CD44, and CD73) and the absence of CD11b, CD19, and HLA-DR by using a set of fluorescently-labeled antibodies specific for the characterization of human MSCs (BD Biosciences) using a MoFlo flow cytometry (Beckman Coulter).
- MSCs were cultured in ⁇ -MEM media supplemented with 10% (v/v) fetal bovine serum (FBS, Hyclone), 10% (v/v) Horse Serum (Hyclone) and 5 mM L-glutamine (Gibco). Cultures at 70% confluence were washed twice with PBS and incubated with serum-free media supplemented with 2 mM L-glutamine for 24 hours under standard culture conditions.
- FBS fetal bovine serum
- Hyclone Horse Serum
- Gibco 5 mM L-glutamine
- Conditioned media were collected from nearly confluent cultures of human MSCs over 24-48 hours or over a period of 3-4 days (in microparticle-depleted FBS cultures) and cells and debris were removed by differential centrifugations at 400 ⁇ g for 5 min, at 2,000 ⁇ g for 10 min, and at 13,000 ⁇ g for 30 min.
- the clarified conditioned media were subsequently filtered through a 0.2 ⁇ m filter unit and concentrated at least 10-fold using a tangential flow filtration system using 100 kD or 300 kD or 500 kD cutoff. Protein levels in the conditioned media were determined by Bradford assay (Bio-Rad).
- MSC exosomes were isolated from the concentrated conditioned media by banding on a 10%-60% step gradient of Iodixanol by centrifugation at 100k ⁇ g for 3.5 hours. Exosomes were further isolated from the conditioned media by differential centrifugation, occasionally followed by a 30% sucrose cushion or sucrose velocity gradients. The particle number of isolated exosome preparations was determined by Nanosight.
- Exosome preparations were separated on 12% polyacrylamide gel and then transferred onto 0.45 ⁇ m PVDF membrane (Millipore). Goat polyclonal anti-CD63 (1:1,000; Santa Cruz) antibody, polyclonal rabbit anti-CD81 (1:1,000, Santa Cruz), and monoclonal anti-Dicer (1:1,000, Abcam) were used. Primary antibodies against ALIX, FLOT-1, TSG101, TGF ⁇ R2, SMAD, CD105, CD9, CD81, CAV1, EFGR and AKT were also used to identify subpopulations of exosomes.
- Peroxidase-conjugated anti-rabbit secondary antibody (Santa Cruz) was used in 1:20,000 dilution to visualize immunoreactive bands either by the enhanced chemiluminescence reagent (Pierce) or Lumi-LightPLUS (Roche).
- the ImageJ program from NIH was used for quantitation through densitometric analysis after appropriate background subtraction.
- Total exosome RNA was extracted by the method of Chomczynski & Sacchi (1987 Anal Biochem 162:156-159) and 750 ng was used as a template for reverse transcriptase with specific primers for each target microRNA (TaqMan Reverse Transcription Kit, Applied Biosystems, Foster City, Calif.). Each reverse transcription reaction included also the primer for the small nuclear RNA sno202, which was used as an internal control. 37.5 ng cDNA was used for each 20 ⁇ l qPCR reaction with TaqMan universal master mix II with no UNG (Applied Biosystems) in the presence of probes specific for the indicated microRNAs and the internal control (TaqMan microRNA assay, Applied Biosystems). Amplification was performed at 50° C. for 2 min, 95° C. for 10 min, followed by 40 cycles of 95° C. for 15 sec, 60° C. for 1 min, on a StepOne Plus platform (Applied Biosystems).
- mice 8-week-old FVB male mice were either obtained from Charles River Laboratories (Wilmington, Mass.) or were raised in the Animal Facility at Children's Hospital Boston. Mice in each group were exposed to 8.5% oxygen in a Plexiglas chamber (OxyCycler, BioSpherix, Redfield, N.Y.) for variable experimental periods. Ventilation was adjusted to remove CO 2 so that it did not exceed 5,000 ppm (0.5%) (average range 1,000-3,000 ppm). Ammonia was removed by ventilation and activated charcoal filtration through an air purifier. All animal protocols were approved by the Children's Hospital Animal Care and Use Committee.
- MSC exosomes mediate the cytoprotective effect of mesenchymal stem cells on hypoxia-induced pulmonary hypertension.
- Intravenous mouse MEX delivery suppressed the hypoxic pulmonary influx of macrophages and the induction of pro-inflammatory and pro-proliferative mediators and eventually inhibited vascular remodeling and hypoxic pulmonary hypertension in a murine PH model.
- the goal of this study was to investigate whether MSCs isolated from human umbilical cord stroma secrete microvesicles exhibiting similar protective properties, and to characterize the biochemical properties of the therapeutic MSC exosome and study its effect on the vascular cell phenotypic changes triggered by the signals that initiate lung vascular remodeling.
- Exosomes were isolated from tissue culture media conditioned by human mesenchymal stem cells (MSCs).
- MSCs mesenchymal stem cells
- WJ Wharton's jelly
- MSCs were isolated, immunoselected, cultured and their differentiation potential assessed. Negative selections for human WJ-MSCs included CD34 and CD45. MSCs were positive for CD90, CD73, CD105 and CD44.
- MEX One dose of MEX was delivered to animals through tail veil injection and recipient mice were exposed to normobaric hypoxia (8-10% O2) for 2.5 days. A decrease in hypoxia-induced inflammatory markers (for example CCL2, IL6), was used as a metric for the effectiveness of the preparation. The dosage used was equivalent to approximately 10-20 billion particles as measured by NanoSight or approximately equivalent to total exosomes produced by 10-20 million MSCs in monolayer cultures over 24 hrs.
- FIG. 1 A shows hypoxia-induced phosphorylation of AKT and its downstream target mTOR are reduced by WJ-MEX treatment.
- FIG. 1 B lung protein levels of the Inhibitor of DNA-binding/differentiation protein ID1, a direct SMAD-targeted gene and downstream signal of BMPR2, are suppressed by hypoxia but increased with MEX.
- Alpha tubulin serves as normalizing control.
- the presence of more than one population of MEX subtype was investigated by density and velocity ultracentrifugation. Analysis of the MEX preparations through density and velocity ultracentrifugation revealed that the population of extracellular microvesicles produced by MSCs is composed by two types, based on molecular markers ( FIG. 2 & FIG. 3 ). The two types have been termed a-MEX and f-MEX. Exosome biogenesis markers, such as ALIX and TSG101 are preferentially enriched in fractions 12-14 (a-MEX), while tetraspanins CD9 and CD81 and lipid raft markers, such as flotilin1 (FLOT1) and caveolin1 (CAV1) are enriched in fractions 5-8 (f-MEX). Table 1 shows the a-MEX and f-MEX specific markers:
- f-MEX are 30-200 nm in diameter and exhibit typical deep cup shape morphology of exosomes, whereas a-MEX are 30-100 nm, with a translucent and spherical morphology.
- exosome subpopulations highly enriched in a-MEX or f-MEX from bulk exosome preparations obtained from MSC grown in monolayer cultures were adjusted to 45% sucrose, layered on a 60% sucrose cushion and overlayered with a step gradient of 35%-5% sucrose. Preparations were centrifuged for 20 hrs at 180k ⁇ g to separate a-MEX and f-MEX subpopulations. Gradient fractions containing a-MEX or f-MEX were concentrated though ultracentifugation (100k ⁇ g, 3 hrs) and resuspended in PBS or though tangential flow filtration.
- FIG. 6 presents microscopy images depicting the formation of MSC spheroids from both 2-D and 3D culture conditions. Spheroid formation is assumed to represent more physiological conditions than the 2-dimensional monolayer cultures. For MSCs, the spheroid state is assumed to represent the more undifferentiated stem-like state. 3-dimensional culture systems that enhance the tendency to form spheroids are commercially available (specific membranes). MSCs will spontaneously form spheroids outgrowing from monolayer cultures at high density, and can be induced to form spheroids if suspended in culture media (hanging drop technique).
- the hanging drop technique is a well-known method of culture for many cell types. Briefly, MSCs grown in monolayer culture were trypsinized to produce a single cell suspension. 30 ⁇ L of this suspension containing 500,000 cells was applied to the inside surface of a petri dish cover and the cover was placed over a dish containing a small amount of PBS to preserve humidity. The dish with the hanging droplets was placed into a tissue culture incubator for 1-2 days, during which time MSCs aggregated into spheroids. A typical spheroid preparation consisted of 15 million cells divided into 30 droplets.
- a-MEX harbor the TGF receptor and the downstream transcription factor SMAD ( FIG. 2 & FIG. 3 ).
- Addition of TG ⁇ 1 to isolated preparations of a-MEX reveals that the signaling module is functional, since the SMAD molecule within the a-MEX is efficiently and specifically phosphorylated in vitro ( FIG. 10 A ).
- This property is specific for a-MEX ( FIG. 10 B ).
- f-MEX contain the EGF receptor and can phosphorylate endogenous AKT in vitro (not shown).
- FIGS. 11 A to 11 C Human lung fibroblasts, after 3 days serum starvation (0.1% FBS), were stimulated with TGF ⁇ to undergo myofibroblast differentiation, marked by increased alpha-smooth muscle actin (SMA) expression.
- SMA alpha-smooth muscle actin
- FIG. 11 A demonstrates that pre-treatment with hMEX (2 ug/ml) abrogates the effect of TGF ⁇ on alpha-SMA protein levels.
- human lung fibroblasts after 24 h serum starvation were stimulated with TGF ⁇ to induce PAI1, a myofibroblast marker.
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Abstract
Description
TABLE 1 | |||
a-MEX specific markers | f-MEX specific markers | ||
ALIX | FLOT1 | ||
TSG101 | CD9 | ||
TGFβR2 | CD81 | ||
SMADs (1, 2, 3, 5) | CAV1 | ||
CD105 | EFGR | ||
AKT (2, 3) | |||
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Families Citing this family (51)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6204830B2 (en) | 2011-03-11 | 2017-09-27 | チルドレンズ メディカル センター コーポレーション | Methods and compositions related to mesenchymal stem cell exosomes |
CN105658672A (en) | 2013-08-22 | 2016-06-08 | 阿塞勒隆制药公司 | TGF-beta receptor type II variants and uses thereof |
EP3071215B1 (en) | 2013-11-21 | 2020-01-08 | The Brigham and Women's Hospital, Inc. | Compositions and methods for treating pulmonary hypertension |
KR20170005854A (en) | 2014-05-18 | 2017-01-16 | 칠드런'즈 메디컬 센터 코포레이션 | Methods and compositions relating to exosomes |
CA2956256A1 (en) | 2014-08-01 | 2016-02-04 | The Brigham And Women's Hospital, Inc. | Methods and compositions relating to treatment of pulmonary arterial hypertension |
US11160834B2 (en) * | 2015-04-28 | 2021-11-02 | The Texas A&M University System | Scalable production of standardized extracellular vesicles, extracellular vesicle preparations and uses thereof |
US10702581B2 (en) | 2015-05-04 | 2020-07-07 | Ilias Biologics Inc. | Compositions containing protein loaded exosome and methods for preparing and delivering the same |
AU2016301380B2 (en) | 2015-08-04 | 2021-07-01 | Acceleron Pharma Inc. | Methods for treating myeloproliferative disorders |
EP4268892A3 (en) * | 2016-03-02 | 2024-01-24 | University of Pittsburgh- Of the Commonwealth System of Higher Education | Matrix bound nanovesicles and their use |
WO2017152035A1 (en) | 2016-03-03 | 2017-09-08 | Henry Ford Health System | 3-d collagen scaffold-generated exosomes and uses thereof |
CN105861430B (en) * | 2016-04-29 | 2019-07-23 | 南京大学 | A kind of excretion body, the preparation method of excretion body and its application in preparation treatment medication for treating pyemia or preparation |
CN110022887A (en) * | 2016-06-17 | 2019-07-16 | 联合治疗学有限公司 | Extracellular vesica with enhancing effect |
US10946047B2 (en) | 2016-06-17 | 2021-03-16 | United Therapeutics Corporation | Extracellular vesicles with enhanced potency |
EP3494978A4 (en) * | 2016-08-03 | 2020-03-11 | National University Corporation Nagoya University | Amelioration and treatment of chronic lung disease using pluripotent stem cells |
KR101830290B1 (en) * | 2016-08-05 | 2018-02-21 | 한양대학교 에리카산학협력단 | Composition for preventing or treating pulmonary fibrosis comprising exosomes extracted from adipose-derived stem cells |
US11596656B2 (en) | 2016-08-23 | 2023-03-07 | Albert Einstein College Of Medicine | Stem cell-produced microvesicles for treating tendon pathologies |
JP2019528674A (en) * | 2016-09-30 | 2019-10-17 | セレックス ライフ サイエンシズ,インコーポレーテッド | Compositions containing exosomes loaded with proteins and methods for their preparation and delivery |
WO2018085587A1 (en) * | 2016-11-02 | 2018-05-11 | Prockop Darwin J | Exosomes and uses thereof in diseases of the brain |
EP4364799A3 (en) * | 2017-01-11 | 2024-07-17 | Paracelsus Medizinische Privatuniversität Salzburg - Privatstiftung | Mesenchymal stem cell-derived extracellular vesicles and their medical use |
KR101973284B1 (en) * | 2017-01-16 | 2019-04-29 | 사회복지법인 삼성생명공익재단 | Compositions for treating neonatal HIE |
WO2018195308A1 (en) * | 2017-04-19 | 2018-10-25 | Figene, Llc | Stimulation of angiogenesis by fibroblast derived exosomes |
CN107137700B (en) * | 2017-04-27 | 2021-01-12 | 张国瑜 | Composition based on stem cell source exosomes and application of composition in preparation of medicine for treating myocardial infarction |
SI3628049T1 (en) | 2017-05-04 | 2023-10-30 | Acceleron Pharma Inc. | Tgf-beta receptor type ii fusion proteins and uses thereof |
ES2945740T3 (en) | 2017-05-05 | 2023-07-06 | Univ Pittsburgh Commonwealth Sys Higher Education | Matrix-Bound Vesicles (MBV) Ocular Applications |
WO2019004757A2 (en) * | 2017-06-30 | 2019-01-03 | 주식회사 엑소코바이오 | Use of composition comprising stem cell-derived exosome as effective ingredient for prevention or alleviation of pruritus |
CN107349220A (en) * | 2017-07-26 | 2017-11-17 | 深圳市泰华细胞工程有限公司 | A kind of preparation comprising fibroblast excretion body and application thereof |
WO2019035880A1 (en) * | 2017-08-15 | 2019-02-21 | Children's Medical Center Corporation | Purifield mesenchymal stem cell exosomes and uses thereof |
WO2019083201A2 (en) * | 2017-10-24 | 2019-05-02 | 주식회사 엑소코바이오 | Use of composition comprising adipose stem cell-derived exosome as effective ingredient in improving renal function |
GB201718681D0 (en) * | 2017-11-13 | 2017-12-27 | Evox Therapeutics Ltd | Protein engineered extracellular vesicles |
US12036325B2 (en) | 2017-12-14 | 2024-07-16 | Mayo Foundation For Medical Education And Research | Purified exosome products, method of making, and methods of using |
CN108318688B (en) * | 2018-01-10 | 2019-08-06 | 浙江大学 | Smad3 albumen is as the application of molecular labeling, liver cancer detection kit in peripheral blood excretion body |
US11938154B2 (en) | 2018-02-27 | 2024-03-26 | Musc Foundation For Research Development | Compositions and methods for treating and/or preventing sepsis and/or inflammatory conditions |
KR102015502B1 (en) | 2018-03-29 | 2019-08-28 | 아키소스템바이오스트래티지스(주) | A method for the isolation of stem cells from human umbilical cords |
IL277447B2 (en) | 2018-04-10 | 2024-04-01 | Brainstorm Cell Therapeutics Ltd | Cell-type specific exosomes and use thereof |
EP3781131A4 (en) * | 2018-04-19 | 2022-06-01 | Board of Regents, The University of Texas System | Therapeutic modulation of tumor suppressors using exosomes |
JP2021523106A (en) * | 2018-04-30 | 2021-09-02 | ザ チルドレンズ メディカル センター コーポレーション | Mesenchymal stromal cell exosomes and their use |
CN108865985A (en) * | 2018-06-22 | 2018-11-23 | 山东省职业卫生与职业病防治研究院 | A kind of method of the pre- epithelial-mesenchymal conversion of stem cell source excretion soma |
CN109266603A (en) * | 2018-08-29 | 2019-01-25 | 浙江大学 | It is a kind of improve heart infarction curative effect excretion body and application |
CN110876734A (en) * | 2018-09-06 | 2020-03-13 | 杨昆德 | Formulations comprising extracellular vesicles, methods for preparing the same, and uses thereof |
CN109596841B (en) * | 2019-01-14 | 2020-04-14 | 浙江大学 | Application of exosome T β RII protein as marker in preparation of breast cancer detection kit |
KR102300686B1 (en) | 2019-02-15 | 2021-09-08 | 이귀선 | An electric muscle stimuation device including a probe for detecting an emg signal generated by electric stimulation of a motor point |
CN110115769A (en) * | 2019-04-08 | 2019-08-13 | 浙江大学 | A kind of Brain targeting excretion body and its preparation method and application |
US20240024220A1 (en) * | 2019-05-11 | 2024-01-25 | Youngsuk Yi | Neurotoxin compositions and methods |
TW202122569A (en) * | 2019-08-09 | 2021-06-16 | 日商宇部興產股份有限公司 | Cell culturing method using small-piece porous membrane |
JP2023513370A (en) * | 2020-02-13 | 2023-03-30 | フィジーン、エルエルシー | Treatment of cerebral palsy with fibroblasts |
US20240000850A1 (en) * | 2020-04-08 | 2024-01-04 | Figene, Llc | Methods and compositions for allergy and asthma treatment using fibroblasts |
JP6967308B1 (en) * | 2020-06-30 | 2021-11-17 | 国立大学法人高知大学 | Cranial nerve disorder therapeutic agent containing tissue cell culture supernatant derived from fetal appendages |
CN114377215B (en) * | 2020-10-16 | 2023-01-31 | 生物岛实验室 | Hernia patch with interface modification and preparation method thereof |
CN115212234B (en) * | 2021-10-22 | 2023-11-10 | 武汉大学中南医院 | Application of exosomes derived from reticulocytes in preparation of drugs for treating and/or preventing sepsis acute kidney injury |
WO2023182507A1 (en) * | 2022-03-24 | 2023-09-28 | 北海道公立大学法人 札幌医科大学 | Pharmaceutical composition, method for producing three-dimensional culture of mesenchymal stem cells, method for producing exosomes, and method for producing pharmaceutical composition |
CN115109741A (en) * | 2022-05-17 | 2022-09-27 | 华中农业大学 | Rapid separation method of lipid raft |
Citations (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6685911B1 (en) | 1997-07-16 | 2004-02-03 | Institut National De La Sante Et De La Recherche Medicale | Sensitization process for antigen-presenting cells and means for implementing the process |
US20040214783A1 (en) | 2002-05-08 | 2004-10-28 | Terman David S. | Compositions and methods for treatment of neoplastic disease |
WO2006071796A2 (en) | 2004-12-23 | 2006-07-06 | Discovery Laboratories, Inc. | Pulmonary surfactant formulations |
US20060286089A1 (en) | 2005-04-08 | 2006-12-21 | Xcyte Therapies, Inc. | Compositions and methods for the treatment of burns and sepsis |
WO2007027156A1 (en) | 2005-09-02 | 2007-03-08 | Agency For Science, Technology And Research | Method of deriving mesenchymal stem cells |
WO2008020815A1 (en) | 2006-08-15 | 2008-02-21 | Agency For Science, Technology And Research | Mesenchymal stem cell conditioned medium |
WO2008060788A2 (en) | 2006-10-11 | 2008-05-22 | The General Hospital Corporation | Compositions, methods, and devices for treating liver disease |
WO2009105044A1 (en) | 2008-02-22 | 2009-08-27 | Agency For Science, Technology And Research (A*Star) | Mesenchymal stem cell particles |
US20100003272A1 (en) | 2007-01-11 | 2010-01-07 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Method for Expanding Monocytes |
CN101890050A (en) | 2010-07-14 | 2010-11-24 | 江苏大学 | Human umbilical cordmesenchymal stem cell-derived exosome and application thereof |
US20110014251A1 (en) | 2008-01-04 | 2011-01-20 | Lydac Neuroscience Limited | Microvesicles |
WO2011010966A1 (en) | 2009-07-23 | 2011-01-27 | Agency For Science, Technology And Research (A*Star) | Pre-natal mesenchymal stem cells |
WO2011053257A2 (en) | 2009-11-02 | 2011-05-05 | Agency For Science, Technology And Research (A*Star) | Methods of monitoring cellular states |
KR20120002361A (en) | 2010-06-30 | 2012-01-05 | 성균관대학교산학협력단 | Composition for treating pulmonary disease comprising mesenchymal stem cell-conditioned media |
WO2012115885A1 (en) | 2011-02-22 | 2012-08-30 | Caris Life Sciences Luxembourg Holdings, S.A.R.L. | Circulating biomarkers |
US20130143314A1 (en) | 2010-08-13 | 2013-06-06 | The University Court Of The University Of Glasgow | Therapeutic uses of microvesicles and related micrornas |
US8476017B2 (en) | 2004-06-02 | 2013-07-02 | Proxy Life Sciene Holdings, Inc. | Microvesicle-based compositions and methods |
WO2013150303A1 (en) | 2012-04-03 | 2013-10-10 | Reneuron Limited | Stem cell microparticles |
WO2014028763A1 (en) | 2012-08-15 | 2014-02-20 | The University Of Chicago | Exosome-based therapeutics against neurodegenerative disorders |
US20140065240A1 (en) | 2011-03-11 | 2014-03-06 | S. Alexander Mitsialis | Methods and compositions relating to mesenchymal stem cell exosomes |
WO2014125277A1 (en) | 2013-02-12 | 2014-08-21 | Reneuron Limited | Method of producing microparticles |
US20150017122A1 (en) | 2011-12-21 | 2015-01-15 | Corion Biotech S.R.L. | Conditioned medium obtained from placental mesenchymal stem cells and use thereof in the therapeutic treatment of preeclampsia |
WO2015179227A1 (en) | 2014-05-18 | 2015-11-26 | Children's Medical Center Corporation | Methods and compositions relating to exosomes |
WO2016043654A1 (en) | 2014-09-15 | 2016-03-24 | Agency For Science, Technology And Research | Methods of treating graft versus host disease (gvhd) or epidermolysis bullosa (eb) with exosomes |
JP2016516768A (en) | 2013-04-12 | 2016-06-09 | サミル・エル・アンダロッシ | Therapeutic delivery vesicles |
US20160190430A1 (en) | 2013-08-07 | 2016-06-30 | Pi Ceramic Gmbh Keramische Technologien Und Bauelemente | Piezoceramic material with reduced lead content |
CN105769916A (en) | 2016-04-29 | 2016-07-20 | 南京大学 | Application of mesenchymal stem cell-derived exosome in preparing drug or preparation for treating preeclampsia |
US20160220613A1 (en) | 2013-09-16 | 2016-08-04 | Agency For Science, Technology And Research | Method |
US9427450B2 (en) | 2012-01-31 | 2016-08-30 | Xon Cells, Inc. | Therapeutic immune modulation by stem cell secreted exosomes |
US20170360840A1 (en) | 2016-06-17 | 2017-12-21 | United Therapeutics Corporation | Extracellular vesicles with enhanced potency |
WO2018131779A1 (en) | 2017-01-16 | 2018-07-19 | 사회복지법인 삼성생명공익재단 | Composition for treating neonatal hie |
WO2018183825A1 (en) | 2017-03-31 | 2018-10-04 | Wisconsin Alumni Research Foundation | Generation of therapeutic cells using extracellular components of target organs |
WO2019217646A1 (en) | 2018-05-09 | 2019-11-14 | Children's Medical Center Corporation | Mesenchymal stromal cell exosome -treated monocytes and uses thereof |
WO2019217091A1 (en) | 2018-04-30 | 2019-11-14 | Children's Medical Center Corporation | Mesenchymal stromal cell exosomes and uses thereof |
WO2020051362A1 (en) | 2018-09-05 | 2020-03-12 | Children's Medical Center Corporation | Use of mesenchymal stromal cell exosomes in antenatal therapy |
US20210128630A1 (en) | 2017-08-15 | 2021-05-06 | Children's Medical Center Corporation | Purified mesenchymal stem cell exosomes and uses thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103797131A (en) * | 2011-06-16 | 2014-05-14 | 卡里斯生命科学卢森堡控股有限责任公司 | Biomarker compositions and methods |
KR101399056B1 (en) * | 2012-04-16 | 2014-05-27 | 연세대학교 산학협력단 | Pharmaceutical Compositions For Preventing or Treating Neuronal Diseases Comprising Stem Cell-derived Microvesicles as Active Ingredient |
-
2015
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- 2015-05-15 CA CA2949083A patent/CA2949083C/en active Active
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-
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- 2020-03-10 US US16/814,044 patent/US11759481B2/en active Active
- 2020-10-01 JP JP2020167150A patent/JP2021020908A/en active Pending
Patent Citations (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6685911B1 (en) | 1997-07-16 | 2004-02-03 | Institut National De La Sante Et De La Recherche Medicale | Sensitization process for antigen-presenting cells and means for implementing the process |
US20040214783A1 (en) | 2002-05-08 | 2004-10-28 | Terman David S. | Compositions and methods for treatment of neoplastic disease |
US8476017B2 (en) | 2004-06-02 | 2013-07-02 | Proxy Life Sciene Holdings, Inc. | Microvesicle-based compositions and methods |
WO2006071796A2 (en) | 2004-12-23 | 2006-07-06 | Discovery Laboratories, Inc. | Pulmonary surfactant formulations |
JP2008525490A (en) | 2004-12-23 | 2008-07-17 | ディスカバリー ラボラトリーズ,インコーポレイテッド | Lung surfactant formulation |
US20060286089A1 (en) | 2005-04-08 | 2006-12-21 | Xcyte Therapies, Inc. | Compositions and methods for the treatment of burns and sepsis |
WO2007027156A1 (en) | 2005-09-02 | 2007-03-08 | Agency For Science, Technology And Research | Method of deriving mesenchymal stem cells |
WO2008020815A1 (en) | 2006-08-15 | 2008-02-21 | Agency For Science, Technology And Research | Mesenchymal stem cell conditioned medium |
WO2008060788A2 (en) | 2006-10-11 | 2008-05-22 | The General Hospital Corporation | Compositions, methods, and devices for treating liver disease |
US20100003272A1 (en) | 2007-01-11 | 2010-01-07 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Method for Expanding Monocytes |
US20110014251A1 (en) | 2008-01-04 | 2011-01-20 | Lydac Neuroscience Limited | Microvesicles |
US20110003008A1 (en) | 2008-02-22 | 2011-01-06 | Agency For Science, Technology And Research (A*Star) | Mesenchymal stem cell particles |
KR20100122087A (en) | 2008-02-22 | 2010-11-19 | 에이전시 포 사이언스, 테크놀로지 앤드 리서치 | Mesenchymal stem cell particles |
WO2009105044A1 (en) | 2008-02-22 | 2009-08-27 | Agency For Science, Technology And Research (A*Star) | Mesenchymal stem cell particles |
US20150190430A1 (en) | 2008-02-22 | 2015-07-09 | Agency For Science, Technology And Research (A*Star) | Mesenchymal stem cell particles |
WO2011010966A1 (en) | 2009-07-23 | 2011-01-27 | Agency For Science, Technology And Research (A*Star) | Pre-natal mesenchymal stem cells |
WO2011053257A2 (en) | 2009-11-02 | 2011-05-05 | Agency For Science, Technology And Research (A*Star) | Methods of monitoring cellular states |
KR20120002361A (en) | 2010-06-30 | 2012-01-05 | 성균관대학교산학협력단 | Composition for treating pulmonary disease comprising mesenchymal stem cell-conditioned media |
CN101890050A (en) | 2010-07-14 | 2010-11-24 | 江苏大学 | Human umbilical cordmesenchymal stem cell-derived exosome and application thereof |
US20130143314A1 (en) | 2010-08-13 | 2013-06-06 | The University Court Of The University Of Glasgow | Therapeutic uses of microvesicles and related micrornas |
WO2012115885A1 (en) | 2011-02-22 | 2012-08-30 | Caris Life Sciences Luxembourg Holdings, S.A.R.L. | Circulating biomarkers |
US20220096560A1 (en) | 2011-03-11 | 2022-03-31 | Children's Medical Center Corporation | Methods and compositions relating to mesenchymal stem cell exosomes |
US20180221412A1 (en) | 2011-03-11 | 2018-08-09 | Children's Medical Center Corporation | Methods and compositions relating to mesenchymal stem cell exosomes |
US20140065240A1 (en) | 2011-03-11 | 2014-03-06 | S. Alexander Mitsialis | Methods and compositions relating to mesenchymal stem cell exosomes |
CN103648509A (en) | 2011-03-11 | 2014-03-19 | 儿童医学中心公司 | Methods and compositions relating to mesenchymal stem cell exosomes |
JP2014507482A (en) | 2011-03-11 | 2014-03-27 | チルドレンズ メディカル センター コーポレーション | Methods and compositions related to mesenchymal stem cell exosomes |
US9901600B2 (en) | 2011-03-11 | 2018-02-27 | Children's Medical Center Corporation | Methods and compositions relating to mesenchymal stem cell exosomes |
US20150017122A1 (en) | 2011-12-21 | 2015-01-15 | Corion Biotech S.R.L. | Conditioned medium obtained from placental mesenchymal stem cells and use thereof in the therapeutic treatment of preeclampsia |
US9427450B2 (en) | 2012-01-31 | 2016-08-30 | Xon Cells, Inc. | Therapeutic immune modulation by stem cell secreted exosomes |
WO2013150303A1 (en) | 2012-04-03 | 2013-10-10 | Reneuron Limited | Stem cell microparticles |
WO2014028763A1 (en) | 2012-08-15 | 2014-02-20 | The University Of Chicago | Exosome-based therapeutics against neurodegenerative disorders |
WO2014125277A1 (en) | 2013-02-12 | 2014-08-21 | Reneuron Limited | Method of producing microparticles |
JP2016507550A (en) | 2013-02-12 | 2016-03-10 | リニューロン・リミテッドReNeuron Limited | Method for producing fine particles |
JP2016516768A (en) | 2013-04-12 | 2016-06-09 | サミル・エル・アンダロッシ | Therapeutic delivery vesicles |
US11274139B2 (en) | 2013-04-12 | 2022-03-15 | Evox Therapeutics Ltd | Therapeutic delivery vesicles |
US20160190430A1 (en) | 2013-08-07 | 2016-06-30 | Pi Ceramic Gmbh Keramische Technologien Und Bauelemente | Piezoceramic material with reduced lead content |
US20160220613A1 (en) | 2013-09-16 | 2016-08-04 | Agency For Science, Technology And Research | Method |
US20170258845A1 (en) | 2013-09-16 | 2017-09-14 | Agency For Science, Technology And Research | Methods of Treating Graft Versus Host Disease (GVHD) or Epidermolysis Bullosa (EB) |
US10624929B2 (en) | 2014-05-18 | 2020-04-21 | Children's Medical Center Corporation | Methods and compositions relating to exosomes |
US20170258840A1 (en) | 2014-05-18 | 2017-09-14 | Children's Medical Center Corporation | Methods and compositions relating to exosomes |
WO2015179227A1 (en) | 2014-05-18 | 2015-11-26 | Children's Medical Center Corporation | Methods and compositions relating to exosomes |
WO2016043654A1 (en) | 2014-09-15 | 2016-03-24 | Agency For Science, Technology And Research | Methods of treating graft versus host disease (gvhd) or epidermolysis bullosa (eb) with exosomes |
CN105769916A (en) | 2016-04-29 | 2016-07-20 | 南京大学 | Application of mesenchymal stem cell-derived exosome in preparing drug or preparation for treating preeclampsia |
US20170360840A1 (en) | 2016-06-17 | 2017-12-21 | United Therapeutics Corporation | Extracellular vesicles with enhanced potency |
WO2018131779A1 (en) | 2017-01-16 | 2018-07-19 | 사회복지법인 삼성생명공익재단 | Composition for treating neonatal hie |
WO2018183825A1 (en) | 2017-03-31 | 2018-10-04 | Wisconsin Alumni Research Foundation | Generation of therapeutic cells using extracellular components of target organs |
US20210128630A1 (en) | 2017-08-15 | 2021-05-06 | Children's Medical Center Corporation | Purified mesenchymal stem cell exosomes and uses thereof |
US20210137989A1 (en) | 2018-04-30 | 2021-05-13 | Children's Medical Center Corporation | Mesenchymal stromal cell exosomes and uses thereof |
WO2019217091A1 (en) | 2018-04-30 | 2019-11-14 | Children's Medical Center Corporation | Mesenchymal stromal cell exosomes and uses thereof |
US20210213056A1 (en) | 2018-05-09 | 2021-07-15 | Children's Medical Center Corporation | Mesenchymal stromal cell exosome-treated monocytes and uses thereof |
WO2019217646A1 (en) | 2018-05-09 | 2019-11-14 | Children's Medical Center Corporation | Mesenchymal stromal cell exosome -treated monocytes and uses thereof |
WO2020051362A1 (en) | 2018-09-05 | 2020-03-12 | Children's Medical Center Corporation | Use of mesenchymal stromal cell exosomes in antenatal therapy |
US20210315940A1 (en) | 2018-09-05 | 2021-10-14 | Children's Medical Center Corporation | Use of mesenchymal stromal cell exosomes in antenatal therapy |
Non-Patent Citations (74)
Title |
---|
Abreu et al., Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases? Stem Cell Res Ther. Apr. 14, 2016;7(1):53. doi: 10.1186/s13287-016-0317-0. |
Ambalavan., Brochopulmonary Dysplasia, Overview. Medscape Online. Updated Mar. 24, 2014. https://reference.medscape.com/article/973717-overview. |
Arslan et al., Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. May 2013;10(3):301-12. doi: 10.1016/j.scr.2013.01.002. Epub Jan. 14, 2013. |
Aslam et al., Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med. Dec. 1, 2009;180(11):1122-30. Epub Aug. 27, 2009. |
Bobrie et al. Diverse subpopulations of vesicles secreted by different intracellular mechanisms are present in exosome preparations obtained by differential ultracentrifugation. J Extracell Vesicles. Apr. 16, 2012;1. doi: 10.3402/jev.v1i0.18397. eCollection 2012. |
Bonfield et al., Adult mesenchymal stem cells: an innovative therapeutic for lung diseases. Discov Med. Apr. 2010;9(47):337-45. Retrieved from the internet May 25, 2012 viahttp://www.discoverymedicine/com/Tracey-L-Bonfield/2010/04/15/adult-mesenchymal-stem-cells-an-innovative-therapeutic-for-lung-diseases/. |
Bouchlaka et al., Human Mesenchymal Stem Cell-Educated Macrophages Are a Distinct High IL-6-Producing Subset that Confer Protection in Graft-versus-Host-Disease and Radiation Injury Models. Biol Blood Marrow Transplant. Jun. 2017;23(6):897-905. |
Bruno et al., Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. May 2009;20(5):1053-67. doi: 10.1681/ASN.2008070798. Epub Apr. 23, 2009. |
Burrello et al., Stem Cell-Derived Extracellular Vesicles and Immune-Modulation. Front Cell Dev Biol. Aug. 22, 2016;4:83. doi: 10.3389/fcell.2016.00083. |
Choi et al., Proteomic analysis of microvesicles derived from human colorectal cancer ascites.Proteomics. Jul. 2011;11(13):2745-51. doi: 10.1002/pmic.201100022. Epub Jun. 1, 2011. |
Collino et al., Exosome and Microvesicle-Enriched Fractions Isolated from Mesenchymal Stem Cells by Gradient Separation Showed Different Molecular Signatures and Functions on Renal Tubular Epithelial Cells. Stem Cell Rev. Apr. 2017;13(2):226-243. doi: 10.1007/s12015-016-9713-1. |
Cruz et al., Systemic Administration of Human Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles Ameliorates Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation in Immunocompetent Mice. Stem Cells Transl Med. Nov. 2015;4(11):1302-16. doi: 10.5966/sctm.2014-0280. Epub Sep. 16, 2015. |
Curley et al., Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat. Thorax. Jun. 2012;67(6):496-501. doi: 10.1136/thoraxjnl-2011-201059. Epub Nov. 21, 2011. |
Ding et al., Transplantation of UC-MSCs on collagen scaffold activates follicles in dormant ovaries of POF patients with long history of infertility. Sci China Life Sci. Dec. 2018;61(12):1554-1565. |
Donnarumma et al., Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer. Oncotarget. Mar. 21, 2017;8(12):19592-19608. |
Dorronsoro et al., Regenerating the injured kidney with human umbilical cord mesenchymal stem cell-derived exosomes. Stem Cell Res Ther. Apr. 25, 2013;4(2):39. doi: 10.1186/scrt187. |
Edgar, Q&A: What are exosomes, exactly? BMC Biology, 2016; vol. 14(46):1-7. doi: 10.1186/s12915-016-0268-z. |
Fuchi et al., Feasibility of placenta-derived mesenchymal stem cells as a tool for studying pregnancy-related disorders. Sci Rep. Apr. 12, 2017;7:46220. |
Gallo et al., The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One. 2012;7(3):e30679. doi: 10.1371/journal.pone.0030679. Epub Mar. 9, 2012. |
Genneback et al., Growth factor stimulation of cardiomyocytes induces changes in the transcriptional contents of secreted exosomes. J Extracell Vesicles. May 17, 2013;2:10.3402. |
Gotts et al., Mesenchymal stem cells and acute lung injury. Crit Care Clin. Jul. 2011;27(3):719-33. Epub May 23, 2011. |
Gupta et al., Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol. Aug. 1, 2007;179(3):1855-63. |
Hansmann et al., Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ. Apr.-Jun. 2012;2(2):170-81. doi: 10.4103/2045-8932.97603. |
Herraiz et al., Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Fertil Steril. May 2018;109(5):908-918.e2. |
Huang et al., Exosomes derived from human adipose mesenchymal stem cells improve ovary function of premature ovarian insufficiency by targeting SMAD. Stem Cell Res Ther. Aug. 9, 2018;9(1):216. |
Ji et al., Proteome profiling of exosomes derived from human primary and metastatic colorectal cancer cells reveal differential expression of key metastatic factors and signal transduction components. Proteomics. May 2013;13(10-11):1672-86. doi: 10.1002/pmic.201200562. |
Jørgensen et al., Extracellular Vesicle (EV) Array: microarray capturing of exosomes and other extracellular vesicles for multiplexed phenotyping. J Extracell Vesicles. Jun. 18, 2013;2. doi: 10.3402/jev.v2i0.20920. eCollection 2013. |
Kalani et al., Exosomes in neurological disease, neuroprotection, repair and therapeutics: problems and perspectives. Neural Regen Res. Oct. 2015;10(10):1565-7. doi: 10.4103/1673-5374.165305. |
Kalra et al., Comparative proteomics evaluation of plasma exosome isolation techniques and assessment of the stability of exosomes in normal human blood plasma. Proteomics. Nov. 2013;13(22):3354-64. doi: 10.1002/pmic.201300282. Epub Oct. 18, 2013. |
Katsha et al., Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. Mol Ther. Jan. 2011;19(1):196-203. Epub Sep. 14, 2010. |
Kim et al., Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hematol. Dec. 2009;37(12):1445-53. |
Kourembanas, S., Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol. 2015;77:13-27. doi: 10.1146/annurev-physiol-021014-071641. Epub Sep. 25, 2014. |
Lai et al., Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. May 2010;4(3):214-22. doi: 10.1016/j.scr.2009.12.003. Epub Jan. 4, 2010. |
Lai et al., Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen Med. Jul. 2011;6(4):481-92. |
Laskin et al., Macrophages and tissue injury: agents of defense or destruction? Annu Rev Pharmacol Toxicol. 2011;51:267-88. doi: 10.1146/annurev.pharmtox.010909.105812. Author Manuscript, 25 pages. |
Lee et al., Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. Nov. 27, 2012;126(22):2601-11. |
Lee et al., Exosomes Mediate the Cytoprotective Effects of Bone Marrow-Derived Stromal Cells (MSCs) on the Hypoxic Lung. American Thoracic Society International Conference Abstracts. May 13-18, 2011. Abstract 21620. |
Lee et al., Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. Jul. 2, 2009;5(1):54-63. doi: 10.1016/j.stem.2009.05.003. |
Lo Sicco et al., Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-Inflammatory Effects: Endorsement of Macrophage Polarization. Stem Cells Transl Med. Mar. 2017;6(3):1018-1028. doi: 10.1002/sctm.16-0363. Epub Jan. 31, 2017. |
Long et al., Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus. Proc Natl Acad Sci U S A. Apr. 25, 2017;114(17):E3536-E3545. doi: 10.1073/pnas.1703920114. |
Lopez-Rodriguez., Immunosuppressive properties of Wharton's jelly derived mesenchymal stromal cells in the treatment of graft versus host disease in rat model. Thesis. Kansas State University. Aug. 1, 2013. pp. 1-20 only. Retrieved on Jul. 9, 2019 from https:krex.k-state.edu/dspace/handle/2097/16331. |
Lou et al., Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp Mol Med. Jun. 16, 2017;49(6):e346. doi: 10.1038/emm.2017.63. |
Mansouri et al., Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes. JCI Insight. Nov. 1, 2019;4(21):e128060. |
Mathivanan et al., Exosomes: extracellular organelles important in intercellular communication. J Proteomics. Sep. 10, 2010;73(10):1907-20. doi: 10.1016/j.jprot.2010.06.006. Epub Jul. 1, 2010. |
Matthay et al., Concise review: Mesenchymal stem (stromal) cells: Biology and preclinical evidence for therapeutic potential for organ dysfunction following trauma or sepsis. Stem Cells. Feb. 17, 2017: 35(2);316-324. |
Matthay et al., Mesenchymal stem cells for acute lung injury: preclinical evidence. Crit Care Med. Oct. 2010;38(10 Suppl):S569-73. |
Mei et al., Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. Sep. 2007;4(9):e269, pp. 1525-1537. |
Mitsialis et al., Stem cell-based therapies for the newborn lung and brain: Possibilities and challenges. Semin Perinatol. Apr. 2016;40(3):138-51. doi: 10.1053/j.semperi.2015.12.002. Epub Jan. 15, 2016. |
Monsel et al., Mesenchymal stem cell derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases. Expert Opin Biol Ther. Jul. 2016;16(7):859-71. |
Monsel et al., Therapeutic Effects of Human Mesenchymal Stem Cell-derived Microvesicles in Severe Pneumonia in Mice. Am J Respir Crit Care Med. Aug. 1, 2015;192(3):324-36. |
Musina et al., Comparison of mesenchymal stem cells obtained from different human tissues. Bull Exp Biol Med. Apr. 2005;139(4):504-9. |
Ophelders et al., Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia. Stem Cells Transl Med. Jun. 2016;5(6):754-63. |
Ortiz et al., Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A. Jul. 8, 2003;100(14):8407-11. Epub Jun. 18, 2003. |
Paine et al., Dentin sialoprotein and dentin phosphoprotein overexpression during amelogenesis. J Biol Chem. Sep. 9, 2005;280(36):31991-8. Epub Jul. 13, 2005. |
Patel et al., Mesenchymal stem cells attenuate hypoxic pulmonary vasoconstriction by a paracrine mechanism. J Surg Res. Dec. 2007;143(2):281-5. Epub Sep. 14, 2007. |
Phinney et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. Oct. 7, 2015;6:8472. |
Pierro et al., Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia. Thorax. May 2013;68(5):475-84. doi: 10.1136/thoraxjnl-2012-202323. Epub Dec. 4, 2012. |
Rojas et al., Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. Aug. 2005;33(2):145-52. Epub May 12, 2005. |
Sdrimas et al., MSC micro vesicles for the treatment of lung disease: a new paradigm for cell-free therapy. Antioxid Redox Signal. Nov. 1, 2014;21(13):1905-15. doi: 10.1089/ars.2013.5784. Epub Feb. 24, 2014. |
Simpson et al., Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics. Jun. 2009;6(3):267-83. doi: 10.1586/epr.09.17. |
Spees et al., Bone marrow progenitor cells contribute to repair and remodeling of the lung and heart in a rat model of progressive pulmonary hypertension. FASEB J. Apr. 2008;22(4):1226-36. |
Strauss et al., Exosome secretion ameliorates lysosomal storage of cholesterol in Niemann-Pick type C disease. J Biol Chem. Aug. 20, 2010;285(34):26279-88. doi: 10.1074/jbc.M110.134775. Epub Jun. 16, 2010. |
Tannetta et al., Characterization of syncytiotrophoblast vesicles in normal pregnancy and pre-eclampsia: expression of Flt-1 and endoglin. PLoS One. 2013;8(2):e56754. |
Tauro et al., Oncogenic H-ras reprograms Madin-Darby canine kidney (MDCK) cell-derived exosomal proteins following epithelial-mesenchymal transition. Mol Cell Proteomics. Aug. 2013;12(8):2148-59. doi: 10.1074/mcp.M112.027086. Epub May 3, 2013. |
Van Haaften et al., Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med. Dec. 1, 2009;180(11):1131-42. Epub Aug. 27, 2009. |
Weiss et al., Embryonic stem cells and repair of lung injury. Mol Ther. Mar. 2010;18(3):460-1. |
Willis et al., Mesenchymal Stem Cell Exosome Treatment Restores Lung Architecture and Ameliorates Pulmonary Hypertension Associated with Bronchopulmonary Dysplasia. Database Biosis. Accession No. PRE201700750539: Experimental Biology Meeting. Apr. 2017;31(1): 327.5. |
Willis et al., Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation. Am J Respir Crit Care Med. Jan. 1, 2018;197(1):104-116. |
Xin et al., Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. Jul. 2012;30(7):1556-64. doi: 10.1002/stem.1129. Author Manuscript, 20 pages. |
Xiong et al., Protective effect of human umbilical cord mesenchymal stem cell exosomes on preserving the morphology and angiogenesis of placenta in rats with preeclampsia. Biomed Pharmacother. Sep. 2018;105:1240-1247. |
Xu et al., Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol. Jul. 2007;293(1):L131-41. Epub Apr. 6, 2007. |
Zhang et al., Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. Jun. 1, 2014;23(11):1233-44. doi: 10.1089/scd.2013.0479. Epub Feb. 10, 2014. |
Zhang et al., Role of bone marrow-derived mesenchymal stem cells in the prevention of hyperoxia-induced lung injury in newborn mice. Cell Biol Int. Jun. 1, 2012;36(6):589-94. doi: 10.1042/CBI20110447. |
Zhang et al., Therapeutic benefit of mesenchymal stem cells in pregnant rats with angiotensin receptor agonistic autoantibody-induced hypertension: Implications for immunomodulation and cytoprotection. Hypertens Pregnancy. Aug. 2017;36(3):247-258. |
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